Inhibitors of influenza viruses replication

ABSTRACT

Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A compound is represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

RELATED APPLICATIONS

This application is a continuation of PCT Application No.PCT/US2012/049097, filed Aug. 1, 2012, which claims priority to U.S.Provisional Application No. 61/513,793, filed Aug. 1, 2011. Each ofthese references is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Influenza spreads around the world in seasonal epidemics, resulting inthe deaths of hundreds of thousands annually—millions in pandemic years.For example, three influenza pandemics occurred in the 20th century andkilled tens of millions of people, with each of these pandemics beingcaused by the appearance of a new strain of the virus in humans. Often,these new strains result from the spread of an existing influenza virusto humans from other animal species.

Influenza is primarily transmitted from person to person via largevirus-laden droplets that are generated when infected persons cough orsneeze; these large droplets can then settle on the mucosal surfaces ofthe upper respiratory tracts of susceptible individuals who are near(e.g. within about 6 feet) infected persons. Transmission might alsooccur through direct contact or indirect contact with respiratorysecretions, such as touching surfaces contaminated with influenza virusand then touching the eyes, nose or mouth. Adults might be able tospread influenza to others from 1 day before getting symptoms toapproximately 5 days after symptoms start. Young children and personswith weakened immune systems might be infectious for 10 or more daysafter onset of symptoms.

Influenza viruses are RNA viruses of the family Orthomyxoviridae, whichcomprises five genera: Influenza virus A, Influenza virus B, Influenzavirus C, Isavirus and Thogoto virus.

The Influenza virus A genus has one species, influenza A virus. Wildaquatic birds are the natural hosts for a large variety of influenza A.Occasionally, viruses are transmitted to other species and may thencause devastating outbreaks in domestic poultry or give rise to humaninfluenza pandemics. The type A viruses are the most virulent humanpathogens among the three influenza types and cause the most severedisease. The influenza A virus can be subdivided into differentserotypes based on the antibody response to these viruses. The serotypesthat have been confirmed in humans, ordered by the number of known humanpandemic deaths, are: H1N1 (which caused Spanish influenza in 1918),H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused HongKong Flu in 1968), H5N1 (a pandemic threat in the 2007-08 influenzaseason), H7N7 (which has unusual zoonotic potential), H1N2 (endemic inhumans and pigs), H9N2, H7N2, H7N3 and H10N7.

The Influenza virus B genus has one species, influenza B virus.Influenza B almost exclusively infects humans and is less common thaninfluenza A. The only other animal known to be susceptible to influenzaB infection is the seal. This type of influenza mutates at a rate 2-3times slower than type A and consequently is less genetically diverse,with only one influenza B serotype. As a result of this lack ofantigenic diversity, a degree of immunity to influenza B is usuallyacquired at an early age. However, influenza B mutates enough thatlasting immunity is not possible. This reduced rate of antigenic change,combined with its limited host range (inhibiting cross species antigenicshift), ensures that pandemics of influenza B do not occur.

The Influenza virus C genus has one species, influenza C virus, whichinfects humans and pigs and can cause severe illness and localepidemics. However, influenza C is less common than the other types andusually seems to cause mild disease in children.

Influenza A, B and C viruses are very similar in structure. The virusparticle is 80-120 nanometers in diameter and usually roughly spherical,although filamentous forms can occur. Unusually for a virus, its genomeis not a single piece of nucleic acid; instead, it contains seven oreight pieces of segmented negative-sense RNA. The Influenza A genomeencodes 11 proteins: hemagglutinin (HA), neuraminidase (NA),nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2 and PB2.

HA and NA are large glycoproteins on the outside of the viral particles.HA is a lectin that mediates binding of the virus to target cells andentry of the viral genome into the target cell, while NA is involved inthe release of progeny virus from infected cells, by cleaving sugarsthat bind the mature viral particles. Thus, these proteins have beentargets for antiviral drugs. Furthermore, they are antigens to whichantibodies can be raised. Influenza A viruses are classified intosubtypes based on antibody responses to HA and NA, forming the basis ofthe H and N distinctions (vide supra) in, for example, H5N1.

Influenza produces direct costs due to lost productivity and associatedmedical treatment, as well as indirect costs of preventative measures.In the United States, influenza is responsible for a total cost of over$10 billion per year, while it has been estimated that a future pandemiccould cause hundreds of billions of dollars in direct and indirectcosts. Preventative costs are also high. Governments worldwide havespent billions of U.S. dollars preparing and planning for a potentialH5N1 avian influenza pandemic, with costs associated with purchasingdrugs and vaccines as well as developing disaster drills and strategiesfor improved border controls.

Current treatment options for influenza include vaccination, andchemotherapy or chemoprophylaxis with anti-viral medications.Vaccination against influenza with an influenza vaccine is oftenrecommended for high-risk groups, such as children and the elderly, orin people that have asthma, diabetes, or heart disease. However, it ispossible to get vaccinated and still get influenza. The vaccine isreformulated each season for a few specific influenza strains but cannotpossibly include all the strains actively infecting people in the worldfor that season. It takes about six months for the manufacturers toformulate and produce the millions of doses required to deal with theseasonal epidemics; occasionally, a new or overlooked strain becomesprominent during that time and infects people although they have beenvaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenzaseason). It is also possible to get infected just before vaccination andget sick with the very strain that the vaccine is supposed to prevent,as the vaccine takes about two weeks to become effective.

Further, the effectiveness of these influenza vaccines is variable. Dueto the high mutation rate of the virus, a particular influenza vaccineusually confers protection for no more than a few years. A vaccineformulated for one year may be ineffective in the following year, sincethe influenza virus changes rapidly over time, and different strainsbecome dominant.

Also, because of the absence of RNA proofreading enzymes, theRNA-dependent RNA polymerase of influenza vRNA makes a single nucleotideinsertion error roughly every 10 thousand nucleotides, which is theapproximate length of the influenza vRNA. Hence, nearly everynewly-manufactured influenza virus is a mutant-antigenic drift. Theseparation of the genome into eight separate segments of vRNA allowsmixing or reassortment of vRNAs if more than one viral line has infecteda single cell. The resulting rapid change in viral genetics producesantigenic shifts and allows the virus to infect new host species andquickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, with neuraminidaseinhibitors being particularly effective, but viruses can developresistance to the standard antiviral drugs.

Thus, there is still a need for drugs for treating influenza infections,such as for drugs with expanded treatment window, and/or reducedsensitivity to viral titer.

SUMMARY OF THE INVENTION

The present invention generally relates to methods of treatinginfluenza, to methods of inhibiting the replication of influenzaviruses, to methods of reducing the amount of influenza viruses, and tocompounds and compositions that can be employed for such methods.

In one embodiment, the present invention is directed to a compoundrepresented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is —F, —Cl, —CF₃, —CN, or CH₃;

X² is —H, —F, or —Cl;

Z¹ is N or CH;

Z² is N or CR⁰;

Z³ is CH or N;

Y is —C(R⁴R⁵)—[C(R⁶R⁷)]_(n)-Q or —C(R⁴)═C(R⁶)-Q;

R⁰ is —H, —F, or CN;

R¹, R², and R³ are each and independently —CH₃, —CH₂F, —CF₃, —C₂H₅,—CH₂CH₂F, —CH₂CF₃; or optionally R² and R³, or R¹, R² and R³, togetherwith the carbon atom to which they are attached, form a 3-10 memberedcarbocyclic ring;

R⁴ and R⁵ are each and independently —H;

R⁶ and R⁷ are each and independently —H, —OH, —CH₃, or —CF₃; or

optionally, R⁵ and R⁷ together with the carbon atoms to which they areattached form a cyclopropane ring; and

each Q is independently —C(O)OR, —OH, —CH₂OH, —S(O)R′, —P(O)(OH)₂,—S(O)₂R′, —S(O)₂—NR″R′″, or a 5-membered heterocycle selected from thegroup consisting of:

J^(Q) is —H, —OH or —CH₂OH;

R is —H or C₁₋₄ alkyl;

R′ is —OH, C₁₋₄ alkyl, or —CH₂C(O)OH;

R″ is —H or —CH₃;

R′″ is —H, a 3-6 membered carbocyclic ring, or C₁₋₄ alkyl optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR^(a) and —C(O)OR^(a);

R^(a) is —H or C₁₋₄ alkyl; and

n is 0 or 1.

In another embodiment, the present invention is directed to apharmaceutical composition comprising a compound disclosed herein (e.g.,a compound represented by any one of Structural Formulae (I)-(X), or apharmaceutically acceptable salt thereof) and a pharmaceuticallyacceptable carrier, adjuvant or vehicle.

In yet another embodiment, the present invention is directed to a methodof inhibiting the replication of influenza viruses in a biologicalsample or patient, comprising the step of administering to saidbiological sample or patient an effective amount of a compound disclosedherein (e.g., a compound represented by any one of Structural Formulae(I)-(X), or a pharmaceutically acceptable salt thereof).

In yet another embodiment, the present invention is directed to a methodof reducing the amount of influenza viruses in a biological sample or ina patient, comprising administering to said biological sample or patientan effective amount of a compound disclosed herein (e.g., a compoundrepresented by any one of Structural Formulae (I)-(X), or apharmaceutically acceptable salt thereof).

In yet another embodiment, the present invention is directed to a methodof method of treating influenza in a patient, comprising administeringto said patient an effective amount of a compound disclosed herein(e.g., a compound represented by any one of Structural Formulae (I)-(X),or a pharmaceutically acceptable salt thereof).

The present invention also provides use of the compounds describedherein for inhibiting the replication of influenza viruses in abiological sample or patient, for reducing the amount of influenzaviruses in a biological sample or patient, or for treating influenza ina patient.

Also provided herein is use of the compounds described herein for themanufacture of a medicament for treating influenza in a patient, forreducing the amount of influenza viruses in a biological sample or in apatient, or for inhibiting the replication of influenza viruses in abiological sample or patient.

Also provided herein are the compounds represented by Structural Formula(XX):

or a pharmaceutically acceptable salt thereof. Without being bound to aparticular theory, the compounds of Structural Formula (XX) can be usedfor synthesizing the compounds of Formula (I). The variables ofStructural Formula (XX) are each and independently as defined herein;and when Z¹ is N, G is trityl (i.e., C(Ph)₃ where Ph is phenyl), andwhen Z¹ is CH, G is tosyl (Ts: CH₃C₆H₄SO₂) or trityl.

The invention also provides methods of preparing a compound representedby Structural Formula (I) or a pharmaceutically acceptable salt thereof.In one embodiment, the methods employ the steps of:

i) reacting compound A:

with compound B:

to form a compound represented by Structural Formula (XX):

andii) deprotecting the G group of the compound of Structural Formula (XX)under suitable conditions to form the compound of Structural Formula(I), wherein:

the variables of Structural Formulae (I) and (XX), and compounds (A) and(B) are independently as defined herein; and

L² is a halogen; and

when Z¹ is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.

In yet another embodiment, the methods employ the steps of:

i) reacting compound K or L:

with compound D: NH₂—Z³(C(R¹R²R³))—Y to form a compound represented byStructural Formula (XX):

andii) deprotecting the G group of the compound of Structural Formula (XX)under suitable conditions to form the compound of Structural Formula(I), wherein:

the variables of Structural Formulae (I) and (XX), and compounds (L),(K), and (D) are each and independently as defined herein; and

when Z¹ is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.

In yet another embodiment, the methods employ the steps of:

i) reacting Compound (G) with Compound (D):

NH₂—Z³(C(R¹R²R³))—Y (D),under suitable conditions to form a compound represented by StructuralFormula (XX):

andii) deprotecting the G group of the compound of Structural Formula (XX)under suitable conditions to form the compound of Structural Formula(I), wherein:

the variables of Structural Formulae (I) and (XX), and Compounds (G) and(D) are each and independently as defined herein;

L¹ is a halogen; and

when Z¹ is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows certain compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention are as described in the claims. In someembodiments, the compounds of the invention are represented by any oneof Structural Formulae (I)-(X), or pharmaceutically acceptable saltsthereof, wherein the variables are each and independently as describedin any one of the claims. In some embodiments, the compounds of theinvention are represented by any chemical formulae depicted in Table 1and FIG. 1, or pharmaceutically acceptable salts thereof. In someembodiments, the compounds of the invention are presented by StructuralFormulae (I)-(X), or a pharmaceutically acceptable salt thereof, whereinthe variables are each and independently as depicted in the chemicalformulae in Table 1 and FIG. 1.

In one embodiment, the compounds of the invention are represented byStructural Formula (I) or pharmaceutically acceptable salts thereof:

wherein the values of the variables of Structural Formula (I) are asdescribed below.

The first set of values of the variables of Structural Formula (I) is asfollows:

X¹ is —F, —Cl, —CF₃, —CN, or CH₃. In one aspect, X¹ is —F, —Cl, or —CF₃.In another aspect, X¹ is —F or —Cl.

X² is —H, —F, —Cl, or —CF₃. In one aspect, X² is —F, —Cl, or —CF₃. Inanother aspect, X² is —F or —Cl.

Z¹ is N or CH. In one aspect, Z¹ is CH. In another aspect, Z¹ is N.

Z² is N or CR⁰. In one aspect, Z² is N, C—F, or C—CN. In another aspect,Z² is N.

Z³ is CH or N. In one aspect, Z³ is CH.

Y is —C(R⁴R⁵)—[C(R⁶R⁷)]_(n)-Q or —C(R⁴)═C(R⁶)-Q.

R⁰ is —H, —F, or CN.

R¹, R², and R³ are each and independently —CH₃, —CH₂F, —CF₃, —C₂H₅,—CH₂CH₂F, —CH₂CF₃; or optionally R² and R³, or R¹, R² and R³, togetherwith the carbon atom to which they are attached, form a 3-10 memberedcarbocyclic ring (including bridged carbocyclic ring, such as adamantlyring). In one aspect, R¹, R², and R³ are each and independently —CH₃, or—C₂H₅, or optionally R² and R³, or R¹, R² and R³, together with thecarbon atom to which they are attached, form a 3-10 membered carbocyclicring. In another aspect, each of R¹, R², and R³ is independently —CH₃,—CH₂F, —CF₃, or —C₂H₅; or R¹ is —CH₃, and R² and R³ together with thecarbon atom to which they are attached form a 3-6 membered carbocyclicring. In another aspect, R¹, R², and R³ are each and independently —CH₃,—CH₂F, —CF₃, or —C₂H₅. In yet another aspect, R¹, R², and R³ are eachand independently —CH₃, or optionally R² and R³, or R¹, R² and R³,together with the carbon atom to which they are attached, form a 3-6membered carbocyclic ring. Specific examples of carbocyclic ring includecyclopropyl, cyclobutyl, cyclopentyl, cylcohexyl, and bridged rings,such as adamantly group. In yet another aspect, R¹, R², and R³ are eachand independently —CH₃.

R⁴ and R⁵ are each and independently —H.

R⁶ and R⁷ are each and independently —H, —OH, —CH₃, or —CF₃; oroptionally, R⁵ and R⁷ together with the carbon atoms to which they areattached form a cyclopropane ring. In one aspect, R⁶ and R⁷ are each andindependently —H, —OH, —CH₃, or —CF₃. In another aspect, R⁶ and R⁷ areeach and independently —H.

Each Q is independently —C(O)OR, —OH, —CH₂OH, —S(O)R′, —P(O)(OH)₂,—S(O)₂R′, —S(O)₂—NR″R′″, or a 5-membered heterocycle selected from thegroup consisting of:

wherein J^(Q) is —H, —OH or —CH₂OH. Specific examples of the 5-memberedheterocycles include:

In one aspect, each Q is independently —C(O)OR, —OH, —CH₂OH, —S(O)₂R′,—S(O)₂—NR″R′″, or a 5-membered heterocycle selected from the groupconsisting of:

In another aspect, each Q is independently —C(O)OH, —OH, —CH₂OH,—S(O)₂R′, —S(O)₂—NR″R′″, or a 5-membered heterocycle selected from thegroup consisting of:

In another aspect, each Q is independently —C(O)OR, —OH, —S(O)₂R′, or—S(O)₂—NR″R′″. In yet another aspect, each Q is independently —C(O)OH,—OH, —S(O)₂R′, or —S(O)₂—NR″R′″.

R is —H or C₁₋₄ alkyl. In one aspect, R is —H.

R′ is —OH, C₁₋₄ alkyl, or —CH₂C(O)OH. In one aspect, R′ is —OH or—CH₂C(O)OH.

R″ is —H or —CH₃. In one aspect, R″ is —H.

R′″ is —H, a 3-6 membered carbocyclic ring, or C₁₋₄ alkyl optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, —OR^(a) and —C(O)OR^(a). In one aspect, R′″ is—H, a 3-6 membered carbocyclic ring, or optionally substituted C₁₋₄alkyl. In another aspect, R′″ is —H or optionally substituted C₁₋₄alkyl.

R^(a) is —H or C₁₋₄ alkyl. In one aspect, R^(a) is —H.

n is 0 or 1.

The second set of values of the variables of Structural Formula (I) isas follows:

X¹ is —F or —Cl.

X² is —F or —Cl.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The third set of values of the variables of Structural Formula (I) is asfollows:

X¹ is —F or —Cl.

Z¹ is CH.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The fourth set of values of the variables of Structural Formula (I) isas follows:

X² is —F or —Cl.

Z¹ is CH.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The fifth set of values of the variables of Structural Formula (I) is asfollows:

X¹ is —F or —Cl.

Z¹ is N

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The sixth set of values of the variables of Structural Formula (I) is asfollows:

X² is —F or —Cl.

Z¹ is N

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The seventh set of values of the variables of Structural Formula (I) isas follows:

X¹ is —F or —Cl.

X² is —F or —Cl.

Z¹ is CH.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The eighth set of values of the variables of Structural Formula (I) isas follows:

X¹ is —F or —Cl.

X² is —F or —Cl.

Z¹ is N.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The ninth set of values of the variables of Structural Formula (I) is asfollows:

X¹ is —F or —Cl.

Z² is N, C—F, or C—CN.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The tenth set of values of the variables of Structural Formula (I) is asfollows:

X² is —F or —Cl

Z² is N, C—F, or C—CN.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The eleventh set of values of the variables of Structural Formula (I) isas follows:

Z¹ is CH.

Z² is N, C—F, or C—CN.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The eleventh set of values of the variables of Structural Formula (I) isas follows:

Z¹ is N.

Z² is N, C—F, or C—CN.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The twelfth set of values of the variables of Structural Formula (I) isas follows:

X¹ is —F or —Cl.

X² is —F or —Cl.

Z¹ is N.

Z² is N, C—F, or C—CN.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The thirteenth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, and Z² are each and independently as described above in anyone of the first through twelfth sets of values of the variables ofStructural Formula (I).

Each of R¹, R², and R³ is independently —CH₃, —CH₂F, —CF₃, or —C₂H₅; orR¹ is —CH₃, and R² and R³ together with the carbon atom to which theyare attached form a 3-6 membered carbocyclic ring.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The fourteenth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, Z², R¹, R², and R³ are each and independently as describedabove in any one of the first through thirteenth sets of values of thevariables of Structural Formula (I).

R⁶ and R⁷ are each and independently —H, —OH, —CH₃, or —CF₃.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The fifteenth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R⁶, and R⁷ are each and independently asdescribed above in any one of the first through fourteenth sets ofvalues of the variables of Structural Formula (I).

Each Q is independently —C(O)OR, —OH, —CH₂OH, —S(O)₂R′, —S(O)₂—NR″R′″,or a 5-membered heterocycle selected from the group consisting of:

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The sixteenth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R⁶, and R⁷ are each and independently asdescribed above in any one of the first through fourteenth sets ofvalues of the variables of Structural Formula (I).

Each Q independently is —C(O)OR, —OH, —S(O)₂R′, or —S(O)₂—NR″R′″.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The seventeenth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R⁶, and R⁷ are each and independently asdescribed above in any one of the first through fourteenth sets ofvalues of the variables of Structural Formula (I).

Each Q independently is —C(O)OH, —OH, —S(O)₂R′, or —S(O)₂—NR″R′″.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The eighteenth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R⁶, and R⁷ are each and independently asdescribed above in any one of the first through fourteenth sets ofvalues of the variables of Structural Formula (I).

Each Q independently is —C(O)OH, —S(O)₂R′, or —S(O)₂—NR″R′″.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The nineteenth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R⁶, R⁷, and Q are each and independently asdescribed above in any one of the first through sixteenth sets of valuesof the variables of Structural Formula (I).

R′ is —OH or —CH₂C(O)OH.

R″ is —H.

R′″ is —H, a 3-6 membered carbocyclic ring, or optionally substitutedC₁₋₄ alkyl.

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

The twentieth set of values of the variables of Structural Formula (I)is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R⁶, and R⁷ are each and independently asdescribed above in any one of the first through sixteenth sets of valuesof the variables of Structural Formula (I).

Each Q independently is —C(O)OH, —S(O)₂OH, —S(O)₂CH₂C(O)OH,—S(O)₂—NH(C₁₋₄ alkyl).

Values of the other variables are each and independently as describedabove in the first set of values of the variables of Structural Formula(I).

In another embodiment, the compounds of the invention are represented byany one of Structural Formulae (II)-(V), or pharmaceutically acceptablesalts thereof:

wherein values of the variables of Structural Formulae (II)-(V) are eachand independently as described above in any one of the first throughtwentieth sets of values of the variables of Structural Formula (I).

In another embodiment, the compounds of the invention are represented byany one of the Structural Formulae (VI)-(X), or pharmaceuticallyacceptable salts thereof:

or a pharmaceutically acceptable salt thereof, wherein: R¹, R², and R³are each and independently —CH₃, —CH₂F, —CF₃, —C₂H₅, —CH₂CH₂F, —CH₂CF₃;and ring P is 3-6 membered carbocyclic ring; and wherein values of theother variables of Structural Formulae (VI) and (X) are each andindependently as described above in any one of the first throughtwentieth sets of values of the variables of Structural Formula (I).

The twenty first set of values of the variables of Structural Formulae(II)-(X) is as follows:

R is H;

R′ is —OH or —CH₂C(O)OH.

R″ is —H.

R′″ is —H, a 3-6 membered carbocyclic ring, or optionally substitutedC₁₋₄ alkyl.

Values of the other variables are each and independently as describedabove.

It is noted that, for example, Structural Formulae (VI), (VIII), and(IX) can also be shown as follows,

respectively:

In yet another embodiment, the compounds of the invention arerepresented by any one of Structural Formulae (I)-(X) or apharmaceutically acceptable salt thereof, wherein values of thevariables are each and independently as shown in the compounds of Table1 or FIG. 1.

In yet another embodiment, the compounds of the invention arerepresented by any one of the structural formulae depicted in Table 1and FIG. 1, or a pharmaceutically acceptable salt thereof.

As used herein, a reference to compound(s) of the invention (forexample, the compound(s) of Structural Formula (I), or compound(s) ofclaim 1) will include pharmaceutically acceptable salts thereof.

The compounds of the invention described herein can be prepared by anysuitable method known in the art. For example, they can be prepared inaccordance with procedures described in WO 2005/095400, WO 2007/084557,WO 2010/011768, WO 2010/011756, WO 2010/011772, WO 2009/073300, andPCT/US2010/038988 filed on Jun. 17, 2010. For example, the compoundsshown in Table 1 and FIG. 1 and the specific compounds depicted abovecan be prepared by any suitable method known in the art, for example, WO2005/095400, WO 2007/084557, WO 2010/011768, WO 2010/011756, WP2010/011772, WO 2009/073300, and PCT/US2010/038988, and by the exemplarysyntheses described below under Exemplification.

The present invention provides methods of preparing a compoundrepresented by any one of Structural Formulae (I)-(X). In oneembodiment, the compounds of the invention can be prepared as depictedin General Schemes 1-4. Any suitable condition(s) known in the art canbe employed in the invention for each step depicted in the schemes.

In a specific embodiment, as shown in General Scheme 1, the methodscomprise the step of reacting Compound (A) with Compound (B) undersuitable conditions to form a compound of Structural Formula (XX),wherein each of L¹ and L² independently is a halogen (F, Cl, Br, or I),G is trityl and the remaining variables of Compounds (A), (B) andStructural Formula (XX) are each and independently as described abovefor Structural Formulae (I)-(X). Typical examples for L¹ and L² are eachand independently Cl or Br. The methods further comprise the step ofdeprotecting the G group under suitable conditions to form the compoundsof Structural Formula (I). Any suitable condition(s) known in the artcan be employed in the invention for each step depicted in the schemes.For example, any suitable condition described in WO 2005/095400 and WO2007/084557 for the coupling of a dioxaboraolan with a chloro-pyrimidinecan be employed for the reaction between Compounds (A) and (B).Specifically, the reaction between compounds (A) and (B) can beperformed in the presence of Pd(PPh₃)₄ or Pd₂(dba)₃ (dba isdibenzylidene acetone). For example, the de-tritylation step can beperformed under an acidic condition (e.g., trifluoroacetic acid (TFA))in the presence of, for example, Et₃SiH (Et is ethyl). Specificexemplary conditions are described in the Exemplification below

Optionally, the method further comprises the step of preparing Compound(A) by reacting Compound (E) with Compound (D). Any suitable conditionsknow in the art can be employed in this step, and Compounds (E) and (D)can be prepared by any suitable method known in the art. Specificexemplary conditions are described in the Exemplification below.

In another specific embodiment, as shown in General Scheme 2, themethods comprise the step of reacting Compound (G) with Compound (D)under suitable conditions to form a compound of Structural Formula (XX),wherein each of L¹ and L² independently is a halogen (F, Cl, Br, or I),G is trityl, and the remaining variables of Compounds (G), (D) andStructural Formula (XX) are each and independently as described abovefor Structural Formulae (I)-(X). Typical examples for L¹ and L² are eachand independently Cl or Br. The methods further comprise the step ofdeprotecting the G group under suitable conditions to form the compoundsof Structural Formula (I). Any suitable condition(s) known in the artcan be employed in the invention for each step depicted in the schemes.For example, any suitable amination condition known in the art can beemployed in the invention for the reaction of Compounds (G) and (D), andany suitable condition for deprotecting a Tr group can be employed inthe invention for the deprotection step. For example, the amination stepcan be performed in the presence of a base, such as NEt₃ orN(^(i)Pr)₂Et. For example, the de-tritylation step can be performedunder an acidic condition (e.g., trifluoroacetic acid (TFA)) in thepresence of, for example, Et₃SiH (Et is ethyl). Additional specificexemplary conditions are described in the Exemplification below

Optionally, the method further comprises the step of preparing Compound(G) by reacting Compound (E) with Compound (B). Any suitable conditionsknow in the art can be employed in this step. For example, any suitablecondition described in WO 2005/095400 and WO 2007/084557 for thecoupling of a dioxaboralan with a chloro-pyrimidine can be employed forthe reaction between Compounds (E) and (B). Specifically, the reactionbetween compounds (E) and (B) can be performed in the presence ofPd(PPh₃)₄ or Pd₂(dba)₃ (dba is dibenzylidene acetone). Specificexemplary conditions are described in the Exemplification below.

In yet another specific embodiment, as shown in General Scheme 3, themethods comprise the step of reacting Compound (K) with Compound (D)under suitable conditions to form a compound of Structural Formula (XX),wherein G is trityl and the remaining variables of Compounds (K), (D)and Structural Formula (XX) are each and independently as describedabove for Structural Formulae (I)-(X). The methods further comprise thestep of deprotecting the G group under suitable conditions to form thecompounds of Structural Formula (I). Any suitable condition(s) known inthe art can be employed in the invention for each step depicted in theschemes. For example, any suitable reaction condition known in the art,for example, in WO 2005/095400 and WO 2007/084557 for the coupling of anamine with a sulfinyl group can be employed for the reaction ofCompounds (K) with Compound (D). For example, Compounds (D) and (K) canbe reacted in the presence of a base, such as NEt₃ or N(^(i)Pr)₂(Et).For example, the de-tritylation step can be performed under an acidiccondition (e.g., trifluoroacetic acid (TFA)) in the presence of, forexample, Et₃SiH (Et is ethyl). Additional specific exemplary conditionsare described in the Exemplification below

Optionally, the method further comprises the step of preparing Compound(K) by oxidizing Compound (J), for example, by treatment withmeta-chloroperbenzoic acid.

Optionally, the method further comprises the step of preparing Compound(J) by reacting Compound (H) with Compound (B). Any suitable conditionsknow in the art can be employed in this step. For example, any suitablecondition described in WO 2005/095400 and WO 2007/084557 for thecoupling of a dioxaborolan with a chloro-pyrimidine can be employed forthe reaction between Compounds (H) and (B). Specifically, the reactionbetween compounds (H) and (B) can be performed in the presence ofPd(PPh₃)₄ or Pd₂(dba)₃ (dba is dibenzylidene acetone). Specificexemplary conditions are described in the Exemplification below.

In yet another specific embodiment, as shown in General Scheme 4, themethods comprise the step of reacting Compound (L) with Compound (D)under suitable conditions to form a compound of Structural Formula (XX),wherein G is trityl and the remaining variables of Compounds (L), (D)and Structural Formula (XX) are each and independently as describedabove for Structural Formulae (I)-(X). The methods further comprise thestep of deprotecting the G group under suitable conditions to form thecompounds of Structural Formula (I). Any suitable condition(s) known inthe art can be employed in the invention for each step depicted in theschemes. For example, any suitable reaction condition known in the art,for example, in WO 2005/095400 and WO 2007/084557 for the coupling of anamine with a sulfonyl group can be employed for the reaction ofCompounds (L) with Compound (D). For example, Compounds (D) and (L) canbe reacted in the presence of a base, such as NEt₃ or N(^(i)Pr)₂(Et).For example, the de-tritylation step can be performed under an acidiccondition (e.g., trifluoroacetic acid (TFA)) in the presence of, forexample, Et₃SiH (Et is ethyl). Additional specific exemplary conditionsare described in the Exemplification below

Optionally, the method further comprises the step of preparing Compound(L) by oxidizing Compound (J), for example, by treatment withmeta-chloroperbenzoic acid.

Optionally, the method further comprises the step of preparing Compound(J) by reacting Compound (H) with Compound (B). Reaction conditions areas described above for General Scheme 3.

Compounds (A)-(K) can be prepared by any suitable method known in theart. Specific exemplary synthetic methods of these compounds aredescribed below in the Exemplification. In one embodiment, Compounds(A), (G), (J), (K) and (L) can be prepared as described in GeneralSchemes 1-4.

In some embodiments, the present invention is directed to a compoundrepresented by Structural Formula (XX), wherein the variables ofStructural Formula (XX) are each and independently as defined in any oneof the claims and G is trityl. Specific examples of the compoundsrepresented by Structural formula (XX) are shown below in theExemplification. Some specific examples include: Compounds 3a, 8a, 28a,34a, 39a, 42a, 51a, 57a, 80a, 84a, 90a, 101a, 119a, 144a, 148a, 154a,159a, 170a, 176a, 182a, 184a, 191a, 197a, 207a, and 218a, which areshown in the Exemplification below.

DEFINITIONS AND GENERAL TERMINOLOGY

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausolito: 1999, and “March'sAdvanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as illustrated generallybelow, or as exemplified by particular classes, subclasses, and speciesof the invention. It will be appreciated that the phrase “optionallysubstituted” is used interchangeably with the phrase “substituted orunsubstituted.” In general, the term “substituted”, whether preceded bythe term “optionally” or not, refers to the replacement of one or morehydrogen radicals in a given structure with the radical of a specifiedsubstituent. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of the group. Whenmore than one position in a given structure can be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at each position. When the term“optionally substituted” precedes a list, said term refers to all of thesubsequent substitutable groups in that list. If a substituent radicalor structure is not identified or defined as “optionally substituted”,the substituent radical or structure is unsubstituted. For example, if Xis optionally substituted C₁-C₃alkyl or phenyl; X may be eitheroptionally substituted C₁-C₃ alkyl or optionally substituted phenyl.Likewise, if the term “optionally substituted” follows a list, said termalso refers to all of the substitutable groups in the prior list unlessotherwise indicated. For example: if X is C₁-C₃alkyl or phenyl wherein Xis optionally and independently substituted by J^(X), then bothC₁-C₃alkyl and phenyl may be optionally substituted by J^(X).

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 3” means any one of 0, 1, 2, and 3. As described herein, aspecified number range of atoms includes any integer therein. Forexample, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.

Selection of substituents and combinations of substituents envisioned bythis invention are those that result in the formation of stable orchemically feasible compounds. The term “stable”, as used herein, refersto compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, specifically,their recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week. Only those choicesand combinations of substituents that result in a stable structure arecontemplated. Such choices and combinations will be apparent to those ofordinary skill in the art and may be determined without undueexperimentation.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched), or branched, hydrocarbon chain thatis completely saturated or that contains one or more units ofunsaturation but is non-aromatic. Unless otherwise specified, aliphaticgroups contain 1-20 aliphatic carbon atoms. In some embodiments,aliphatic groups contain 1-10 aliphatic carbon atoms. In otherembodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. Instill other embodiments, aliphatic groups contain 1-6 aliphatic carbonatoms, and in yet other embodiments, aliphatic groups contain 1-4aliphatic carbon atoms. Aliphatic groups may be linear or branched,substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specificexamples include, but are not limited to, methyl, ethyl, isopropyl,n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl andacetylene.

The term “alkyl” as used herein means a saturated straight or branchedchain hydrocarbon. The term “alkenyl” as used herein means a straight orbranched chain hydrocarbon comprising one or more double bonds. The term“alkynyl” as used herein means a straight or branched chain hydrocarboncomprising one or more triple bonds. Each of the “alkyl”, “alkenyl” or“alkynyl” as used herein can be optionally substituted as set forthbelow. In some embodiments, the “alkyl” is C₁-C₆ alkyl or C₁-C₄ alkyl.In some embodiments, the “alkenyl” is C₂-C₆ alkenyl or C₂-C₄ alkenyl. Insome embodiments, the “alkynyl” is C₂-C₆ alkynyl or C₂-C₄ alkynyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or“carbocyclic”) refers to a non-aromatic carbon only containing ringsystem which can be saturated or contains one or more units ofunsaturation, having three to fourteen ring carbon atoms. In someembodiments, the number of carbon atoms is 3 to 10. In otherembodiments, the number of carbon atoms is 4 to 7. In yet otherembodiments, the number of carbon atoms is 5 or 6. The term includesmonocyclic, bicyclic or polycyclic, fused, spiro or bridged carbocyclicring systems. The term also includes polycyclic ring systems in whichthe carbocyclic ring can be “fused” to one or more non-aromaticcarbocyclic or heterocyclic rings or one or more aromatic rings orcombination thereof, wherein the radical or point of attachment is onthe carbocyclic ring. “Fused” bicyclic ring systems comprise two ringswhich share two adjoining ring atoms. Bridged bicyclic group comprisetwo rings which share three or four adjacent ring atoms. Spiro bicyclicring systems share one ring atom. Examples of cycloaliphatic groupsinclude, but are not limited to, cycloalkyl and cycloalkenyl groups.Specific examples include, but are not limited to, cyclohexyl,cyclopropenyl, and cyclobutyl.

The term “heterocycle” (or “heterocyclyl”, or “heterocyclic” or“non-aromatic heterocycle”) as used herein refers to a non-aromatic ringsystem which can be saturated or contain one or more units ofunsaturation, having three to fourteen ring atoms in which one or morering carbons is replaced by a heteroatom such as, N, S, or O and eachring in the system contains 3 to 7 members. In some embodiments,non-aromatic heterocyclic rings comprise up to three heteroatomsselected from N, S and O within the ring. In other embodiments,non-aromatic heterocyclic rings comprise up to two heteroatoms selectedfrom N, S and O within the ring system. In yet other embodiments,non-aromatic heterocyclic rings comprise up to two heteroatoms selectedfrom N and O within the ring system. The term includes monocyclic,bicyclic or polycyclic fused, spiro or bridged heterocyclic ringsystems. The term also includes polycyclic ring systems in which theheterocyclic ring can be fused to one or more non-aromatic carbocyclicor heterocyclic rings or one or more aromatic rings or combinationthereof, wherein the radical or point of attachment is on theheterocyclic ring. Examples of heterocycles include, but are not limitedto, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl,triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl,benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl,tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, including, forexample, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl,benzodithianyl, 3-(1-alkyl)-benzimidazol-2-onyl, and1,3-dihydro-imidazol-2-onyl.

The term “aryl” (or “aryl ring” or “aryl group”) used alone or as partof a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refersto carbocyclic aromatic ring systems. The term “aryl” may be usedinterchangeably with the terms “aryl ring” or “aryl group”.

“Carbocyclic aromatic ring” groups have only carbon ring atoms(typically six to fourteen) and include monocyclic aromatic rings suchas phenyl and fused polycyclic aromatic ring systems in which two ormore carbocyclic aromatic rings are fused to one another. Examplesinclude 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Alsoincluded within the scope of the term “carbocyclic aromatic ring” or“carbocyclic aromatic”, as it is used herein, is a group in which anaromatic ring is “fused” to one or more non-aromatic rings (carbocyclicor heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, or tetrahydronaphthyl, where the radical or point ofattachment is on the aromatic ring.

The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroarylgroup”, “aromatic heterocycle” or “heteroaromatic group”, used alone oras part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”,refer to heteroaromatic ring groups having five to fourteen members,including monocyclic heteroaromatic rings and polycyclic aromatic ringsin which a monocyclic aromatic ring is fused to one or more otheraromatic ring. Heteroaryl groups have one or more ring heteroatoms. Alsoincluded within the scope of the term “heteroaryl”, as it is usedherein, is a group in which an aromatic ring is “fused” to one or morenon-aromatic rings (carbocyclic or heterocyclic), where the radical orpoint of attachment is on the aromatic ring. Bicyclic 6,5 heteroaromaticring, as used herein, for example, is a six membered heteroaromatic ringfused to a second five membered ring, wherein the radical or point ofattachment is on the six membered ring. Examples of heteroaryl groupsinclude pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl,pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, forexample, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl,5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl,4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl,tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl,benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl,acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl,1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl,pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

As used herein, “cyclo”, “cyclic”, “cyclic group” or “cyclic moiety”,include mono-, bi-, and tri-cyclic ring systems includingcycloaliphatic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl,each of which has been previously defined.

As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or11) membered structures that form two rings, wherein the two rings haveat least one atom in common (e.g., 2 atoms in common). Bicyclic ringsystems include bicycloaliphatics (e.g., bicycloalkyl orbicycloalkenyl), bicycloheteroaliphatics, bicyclic carbocyclic aryls,and bicyclic heteroaryls.

As used herein, a “bridged bicyclic ring system” refers to a bicyclicheterocycloalipahtic ring system or bicyclic cycloaliphatic ring systemin which the rings are bridged. Examples of bridged bicyclic ringsystems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system canbe optionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, carbocyclic aryl, heteroaryl,alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl)oxy,heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro,carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkylalkyl)carbonylamino, (carbocyclic aryl)carbonylamino,aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto,alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, “bridge” refers to a bond or an atom or an unbranchedchain of atoms connecting two different parts of a molecule. The twoatoms that are connected through the bridge (usually but not always, twotertiary carbon atoms) are denotated as “bridgeheads”.

As used herein, the term “spiro” refers to ring systems having one atom(usually a quaternary carbon) as the only common atom between two rings.

The term “ring atom” is an atom such as C, N, O or S that is in the ringof an aromatic group, cycloalkyl group or non-aromatic heterocyclicring.

A “substitutable ring atom” in an aromatic group is a ring carbon ornitrogen atom bonded to a hydrogen atom. The hydrogen can be optionallyreplaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atomswhich are shared when two rings are fused. In addition, “substitutablering atom” does not include ring carbon or nitrogen atoms when thestructure depicts that they are already attached to a moiety other thanhydrogen.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

As used herein an optionally substituted aralkyl can be substituted onboth the alkyl and the aryl portion. Unless otherwise indicated as usedherein optionally substituted aralkyl is optionally substituted on thearyl portion.

In some embodiments, an aliphatic or heteroaliphatic group, or anon-aromatic heterocyclic ring may contain one or more substituents.Suitable substituents on the saturated carbon of an aliphatic orheteroaliphatic group, or of a heterocyclic ring are selected from thoselisted above. Other suitable substitutents include those listed assuitable for the unsaturated carbon of a carbocyclic aryl or heteroarylgroup and additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(C₁₋₄ alkyl), ═NNHSO₂(C₁₋₄ alkyl), or ═NR*, whereineach R* is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic. Optional substituents on the aliphatic groupof R* are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄aliphatic groups of R* is unsubstituted.

In some embodiments, optional substituents on the nitrogen of aheterocyclic ring include those used above. Other suitable substituentsinclude —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺,—SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; whereinR⁺ is hydrogen, an optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted —O(Ph), optionallysubstituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur, or, two independent occurrences of R⁺,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺ group is bound, form a 5-8-memberedheterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen,C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄ aliphatic groups of R⁺ is unsubstituted.

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including heteroaralkyl andheteroarylalkoxy and the like) group may contain one or moresubstituents. Suitable substituents on the unsaturated carbon atom of acarbocyclic aryl or heteroaryl group are selected from those listedabove. Other suitable substituents include: halogen; —R^(o); —OR^(o);—SR^(o) ; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionallysubstituted with R^(o); —O(Ph) optionally substituted with R^(o);—(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph), optionallysubstituted with R^(o); —NO₂; —CN; —N(R^(o))₂; —NR^(o)C(O)R^(o);—NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂;—NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o); C(O)N(R^(o))₂;—NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o);—C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂; —OC(O)N(R^(o))₂;—OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o)) R^(o); —S(O)₂R^(o);—S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂;—NR^(o)SO₂R^(o); —N(OR^(o))R^(o); —C(═NH)—N(R^(o))₂; or—(CH₂)₀₋₂NHC(O)R^(o); wherein each independent occurrence of R^(o)isselected from hydrogen, optionally substituted C₁₋₆ aliphatic, anunsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl,—O(Ph), or —CH₂(Ph), or, two independent occurrences of R^(o), on thesame substituent or different substituents, taken together with theatom(s) to which each R^(o) group is bound, form a 5-8-memberedheterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-memberedcycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.Optional substituents on the aliphatic group of R^(o) are selected fromNH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH,O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄aliphatic, CHO, N(CO)(C₁₋₄ aliphatic), C(O)N(C₁₋₄aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R^(o)is unsubstituted.

Non-aromatic nitrogen containing heterocyclic rings that are substitutedon a ring nitrogen and attached to the remainder of the molecule at aring carbon atom are said to be N substituted. For example, an N alkylpiperidinyl group is attached to the remainder of the molecule at thetwo, three or four position of the piperidinyl ring and substituted atthe ring nitrogen with an alkyl group. Non-aromatic nitrogen containingheterocyclic rings such as pyrazinyl that are substituted on a ringnitrogen and attached to the remainder of the molecule at a second ringnitrogen atom are said to be N′ substituted-N-heterocycles. For example,an N′ acyl N-pyrazinyl group is attached to the remainder of themolecule at one ring nitrogen atom and substituted at the second ringnitrogen atom with an acyl group.

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein), may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a3-8-membered cycloalkyl ring. Exemplary rings that are formed when twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) are taken together with the atom(s) to which eachvariable is bound include, but are not limited to the following: a) twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) that are bound to the same atom and are taken togetherwith that atom to form a ring, for example, N(R^(o))₂, where bothoccurrences of R^(o) are taken together with the nitrogen atom to form apiperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) twoindependent occurrences of R^(o) (or R⁺, or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

The term “hydroxyl” or “hydroxy” or “alcohol moiety” refers to —OH.

As used herein, an “alkoxycarbonyl,” which is encompassed by the termcarboxy, used alone or in connection with another group refers to agroup such as (alkyl-O)—C(O)—.

As used herein, a “carbonyl” refers to —C(O)—.

As used herein, an “oxo” refers to ═O.

As used herein, the term “alkoxy”, or “alkylthio”, as used herein,refers to an alkyl group, as previously defined, attached to themolecule through an oxygen (“alkoxy” e.g., —O-alkyl) or sulfur(“alkylthio” e.g., —S-alkyl) atom.

As used herein, the terms “halogen”, “halo”, and “hal” mean F, Cl, Br,or I.

As used herein, the term “cyano” or “nitrile” refer to —CN or —CEN.

The terms “alkoxyalkyl”, “alkoxyalkenyl”, “alkoxyaliphatic”, and“alkoxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more alkoxy groups.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be,substituted with one or more halogen atoms. This term includesperfluorinated alkyl groups, such as —CF₃ and —CF₂CF₃.

The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and“cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more cyano groups. In some embodiments, thecyanoalkyl is (NC)-alkyl-.

The terms “aminoalkyl”, “aminoalkenyl”, “aminoaliphatic”, and“aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more amino groups, wherein the amino groupis as defined above. In some embodiments, the aminoaliphatic is a C1-C6aliphatic group substituted with one or more —NH₂ groups. In someembodiments, the aminoalkyl refers to the structure(R^(X)R^(Y))N-alkyl-, wherein each of R^(X) and R^(Y) independently isas defined above. In some specific embodiments, the aminoalkyl is C1-C6alkyl substituted with one or more —NH₂ groups. In some specificembodiments, the aminoalkenyl is C1-C6 alkenyl substituted with one ormore —NH₂ groups. In some embodiments, the aminoalkoxy is —O(C1-C6alkyl) wherein the alkyl group is substituted with one or more —NH₂groups.

The terms “hydroxyalkyl”, “hydroxyaliphatic”, and “hydroxyalkoxy” meanalkyl, aliphatic or alkoxy, as the case may be, substituted with one ormore —OH groups.

The terms “alkoxyalkyl”, “alkoxyaliphatic”, and “alkoxyalkoxy” meanalkyl, aliphatic or alkoxy, as the case may be, substituted with one ormore alkoxy groups. For example, an “alkoxyalkyl” refers to an alkylgroup such as (alkyl-O)-alkyl-, wherein alkyl is as defined above.

The term “carboxyalkyl” means alkyl substituted with one or more carboxygroups, wherein alkyl and carboxy are as defined above.

The term “protecting group” and “protective group” as used herein, areinterchangeable and refer to an agent used to temporarily block one ormore desired functional groups in a compound with multiple reactivesites. In certain embodiments, a protecting group has one or more, orspecifically all, of the following characteristics: a) is addedselectively to a functional group in good yield to give a protectedsubstrate that is b) stable to reactions occurring at one or more of theother reactive sites; and c) is selectively removable in good yield byreagents that do not attack the regenerated, deprotected functionalgroup. As would be understood by one skilled in the art, in some cases,the reagents do not attack other reactive groups in the compound. Inother cases, the reagents may also react with other reactive groups inthe compound. Examples of protecting groups are detailed in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, ThirdEdition, John Wiley & Sons, New York: 1999 (and other editions of thebook), the entire contents of which are hereby incorporated byreference. The term “nitrogen protecting group”, as used herein, refersto an agent used to temporarily block one or more desired nitrogenreactive sites in a multifunctional compound. Preferred nitrogenprotecting groups also possess the characteristics exemplified for aprotecting group above, and certain exemplary nitrogen protecting groupsare also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in“Protective Groups in Organic Synthesis”, Third Edition, John Wiley &Sons, New York: 1999, the entire contents of which are herebyincorporated by reference.

As used herein, the term “displaceable moiety” or “leaving group” refersto a group that is associated with an aliphatic or aromatic group asdefined herein and is subject to being displaced by nucleophilic attackby a nucleophile.

Unless otherwise indicated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, cis-trans,conformational, and rotational) forms of the structure. For example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers are included inthis invention, unless only one of the isomers is drawn specifically. Aswould be understood to one skilled in the art, a substituent can freelyrotate around any rotatable bonds. For example, a substituent drawn as

also represents

Therefore, single stereochemical isomers as well as enantiomeric,diastereomeric, cis/trans, conformational, and rotational mixtures ofthe present compounds are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.Such compounds, especially deuterium analogs, can also betherapeutically useful.

The terms “a bond” and “absent” are used interchangeably to indicatethat a group is absent.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Pharmaceutically Acceptable Salts, Solvates, Chlatrates, Prodrugs andOther Derivatives

The compounds described herein can exist in free form, or, whereappropriate, as salts. Those salts that are pharmaceutically acceptableare of particular interest since they are useful in administering thecompounds described below for medical purposes. Salts that are notpharmaceutically acceptable are useful in manufacturing processes, forisolation and purification purposes, and in some instances, for use inseparating stereoisomeric forms of the compounds of the invention orintermediates thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tosalts of a compound which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue side effects, such as, toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsdescribed herein include those derived from suitable inorganic andorganic acids and bases. These salts can be prepared in situ during thefinal isolation and purification of the compounds.

Where the compound described herein contains a basic group, or asufficiently basic bioisostere, acid addition salts can be preparedby 1) reacting the purified compound in its free-base form with asuitable organic or inorganic acid and 2) isolating the salt thusformed. In practice, acid addition salts might be a more convenient formfor use and use of the salt amounts to use of the free basic form.

Examples of pharmaceutically acceptable, non-toxic acid addition saltsare salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like.

Where the compound described herein contains a carboxy group or asufficiently acidic bioisostere, base addition salts can be preparedby 1) reacting the purified compound in its acid form with a suitableorganic or inorganic base and 2) isolating the salt thus formed. Inpractice, use of the base addition salt might be more convenient and useof the salt form inherently amounts to use of the free acid form. Saltsderived from appropriate bases include alkali metal (e.g., sodium,lithium, and potassium), alkaline earth metal (e.g., magnesium andcalcium), ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention alsoenvisions the quaternization of any basic nitrogen-containing groups ofthe compounds disclosed herein. Water or oil-soluble or dispersibleproducts may be obtained by such quaternization.

Basic addition salts include pharmaceutically acceptable metal and aminesalts. Suitable metal salts include the sodium, potassium, calcium,barium, zinc, magnesium, and aluminium. The sodium and potassium saltsare usually preferred. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate. Suitable inorganic base addition salts are prepared frommetal bases which include sodium hydride, sodium hydroxide, potassiumhydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide,magnesium hydroxide, zinc hydroxide and the like. Suitable amine baseaddition salts are prepared from amines which are frequently used inmedicinal chemistry because of their low toxicity and acceptability formedical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, ornithine, choline, N,N′-dibenzylethylenediamine,chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine,dehydroabietylamine, N-ethylpiperidine, benzylamine,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and thelike.

Other acids and bases, while not in themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds described herein and theirpharmaceutically acceptable acid or base addition salts.

It should be understood that this invention includesmixtures/combinations of different pharmaceutically acceptable salts andalso mixtures/combinations of compounds in free form andpharmaceutically acceptable salts.

The compounds described herein can also exist as pharmaceuticallyacceptable solvates (e.g., hydrates) and clathrates. As used herein, theterm “pharmaceutically acceptable solvate,” is a solvate formed from theassociation of one or more pharmaceutically acceptable solvent moleculesto one of the compounds described herein. The term solvate includeshydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate,tetrahydrate, and the like).

As used herein, the term “hydrate” means a compound described herein ora salt thereof that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, the term “clathrate” means a compound described hereinor a salt thereof in the form of a crystal lattice that contains spaces(e.g., channels) that have a guest molecule (e.g., a solvent or water)trapped within.

In addition to the compounds described herein, pharmaceuticallyacceptable derivatives or prodrugs of these compounds may also beemployed in compositions to treat or prevent the herein identifieddisorders.

A “pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable ester, salt of an ester or other derivativeor salt thereof of a compound described herein which, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound described herein or an inhibitorily activemetabolite or residue thereof. Particularly favoured derivatives orprodrugs are those that increase the bioavailability of the compoundswhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound described herein. Prodrugs may become active upon such reactionunder biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds ofthe invention that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of compounds described herein that comprise —NO, —NO₂, —ONO,or —ONO₂ moieties. Prodrugs can typically be prepared using well-knownmethods, such as those described by BURGER'S MEDICINAL CHEMISTRY ANDDRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

A “pharmaceutically acceptable derivative” is an adduct or derivativewhich, upon administration to a patient in need, is capable ofproviding, directly or indirectly, a compound as otherwise describedherein, or a metabolite or residue thereof. Examples of pharmaceuticallyacceptable derivatives include, but are not limited to, esters and saltsof such esters. Pharmaceutically acceptable prodrugs of the compoundsdescribed herein include, without limitation, esters, amino acid esters,phosphate esters, metal salts and sulfonate esters.

Uses of Disclosed Compounds

One aspect of the present invention is generally related to the use ofthe compounds described herein or pharmaceutically acceptable salts, orpharmaceutically acceptable compositions comprising such a compound or apharmaceutically acceptable salt thereof, for inhibiting the replicationof influenza viruses in a biological sample or in a patient, forreducing the amount of influenza viruses (reducing viral titer) in abiological sample or in a patient, and for treating influenza in apatient.

In one embodiment, the present invention is generally related to the useof compounds represented by any one of Structural Formulae (I)-(X), orpharmaceutically acceptable salts thereof for any of the uses specifiedabove:

In yet another embodiment, the present invention is directed to the useof any compound selected from the compounds depicted in Table 1 or apharmaceutically acceptable salt thereof, for any of the uses describedabove.

In some embodiments, the compounds are represented by any one ofStructural Formulae (I)-(X), and the variables are each independently asdepicted in the compounds of Table 1.

In yet another embodiment, the compounds described herein orpharmaceutically acceptable salts thereof can be used to reduce viraltitre in a biological sample (e.g. an infected cell culture) or inhumans (e.g. lung viral titre in a patient).

The terms “influenza virus mediated condition”, “influenza infection”,or “Influenza”, as used herein, are used interchangeable to mean thedisease caused by an infection with an influenza virus.

Influenza is an infectious disease that affects birds and mammals causedby influenza viruses. Influenza viruses are RNA viruses of the familyOrthomyxoviridae, which comprises five genera: Influenzavirus A,Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus.Influenzavirus A genus has one species, influenza A virus which can besubdivided into different serotypes based on the antibody response tothese viruses: H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 andH10N7. Influenzavirus B genus has one species, influenza B virus.Influenza B almost exclusively infects humans and is less common thaninfluenza A. Influenzavirus C genus has one species, Influenzavirus Cvirus, which infects humans and pigs and can cause severe illness andlocal epidemics. However, Influenzavirus C is less common than the othertypes and usually seems to cause mild disease in children.

In some embodiments of the invention, influenza or influenza viruses areassociated with Influenzavirus A or B. In some embodiments of theinvention, influenza or influenza viruses are associated withInfluenzavirus A. In some specific embodiments of the invention,Influenzavirus A is H1N1, H2N2, H3N2 or H5N1.

In humans, common symptoms of influenza are chills, fever, pharyngitis,muscle pains, severe headache, coughing, weakness, and generaldiscomfort. In more serious cases, influenza causes pneumonia, which canbe fatal, particularly in young children and the elderly. Although it isoften confused with the common cold, influenza is a much more severedisease and is caused by a different type of virus. Influenza canproduce nausea and vomiting, especially in children, but these symptomsare more characteristic of the unrelated gastroenteritis, which issometimes called “stomach flu” or “24-hour flu”.

Symptoms of influenza can start quite suddenly one to two days afterinfection. Usually the first symptoms are chills or a chilly sensation,but fever is also common early in the infection, with body temperaturesranging from 38-39° C. (approximately 100-103° F.). Many people are soill that they are confined to bed for several days, with aches and painsthroughout their bodies, which are worse in their backs and legs.Symptoms of influenza may include: body aches, especially joints andthroat, extreme coldness and fever, fatigue, Headache, irritatedwatering eyes, reddened eyes, skin (especially face), mouth, throat andnose, abdominal pain (in children with influenza B). Symptoms ofinfluenza are non-specific, overlapping with many pathogens(“influenza-like illness). Usually, laboratory data is needed in orderto confirm the diagnosis.

The terms, “disease”, “disorder”, and “condition” may be usedinterchangeably here to refer to an influenza virus mediated medical orpathological condition.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),specifically a “mammal” including a non-primate (e.g., a cow, pig,horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and aprimate (e.g., a monkey, chimpanzee and a human), and more specificallya human. In one embodiment, the subject is a non-human animal such as afarm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog,cat, guinea pig or rabbit). In a preferred embodiment, the subject is a“human”.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; blood, saliva, urine, feces,semen, tears, or other body fluids or extracts thereof.

As used herein, “multiplicity of infection” or “MOI” is the ratio ofinfectious agents (e.g. phage or virus) to infection targets (e.g.cell). For example, when referring to a group of cells inoculated withinfectious virus particles, the multiplicity of infection or MOI is theratio defined by the number of infectious virus particles deposited in awell divided by the number of target cells present in that well.

As used herein the term “inhibition of the replication of influenzaviruses” includes both the reduction in the amount of virus replication(e.g. the reduction by at least 10%) and the complete arrest of virusreplication (i.e., 100% reduction in the amount of virus replication).In some embodiments, the replication of influenza viruses are inhibitedby at least 50%, at least 65%, at least 75%, at least 85%, at least 90%,or at least 95%.

Influenza virus replication can be measured by any suitable method knownin the art. For example, influenza viral titre in a biological sample(e.g. an infected cell culture) or in humans (e.g. lung viral titre in apatient) can be measured. More specifically, for cell based assays, ineach case cells are cultured in vitro, virus is added to the culture inthe presence or absence of a test agent, and after a suitable length oftime a virus-dependent endpoint is evaluated. For typical assays, theMadin-Darby canine kidney cells (MDCK) and the standard tissue cultureadapted influenza strain, A/Puerto Rico/8/34 can be used. A first typeof cell assay that can be used in the invention depends on death of theinfected target cells, a process called cytopathic effect (CPE), wherevirus infection causes exhaustion of the cell resources and eventuallysis of the cell. In the first type of cell assay, a low fraction ofcells in the wells of a microtiter plate are infected (typically 1/10 to1/1000), the virus is allowed to go through several rounds ofreplication over 48-72 hours, then the amount of cell death is measuredusing a decrease in cellular ATP content compared to uninfectedcontrols. A second type of cell assay that can be employed in theinvention depends on the multiplication of virus-specific RNA moleculesin the infected cells, with RNA levels being directly measured using thebranched-chain DNA hybridization method (bDNA). In the second type ofcell assay, a low number of cells are initially infected in wells of amicrotiter plate, the virus is allowed to replicate in the infectedcells and spread to additional rounds of cells, then the cells are lysedand viral RNA content is measured. This assay is stopped early, usuallyafter 18-36 hours, while all the target cells are still viable. ViralRNA is quantitated by hybridization to specific oligonucleotide probesfixed to wells of an assay plate, then amplification of the signal byhybridization with additional probes linked to a reporter enzyme.

As used herein a “viral titer (or titre)” is a measure of virusconcentration. Titer testing can employ serial dilution to obtainapproximate quantitative information from an analytical procedure thatinherently only evaluates as positive or negative. The titer correspondsto the highest dilution factor that still yields a positive reading; forexample, positive readings in the first 8 serial twofold dilutionstranslate into a titer of 1:256. A specific example is viral titer. Todetermine the titer, several dilutions will be prepared, such as 10⁻¹,10⁻², 10⁻³, . . . , 10⁻⁸. The lowest concentration of virus that stillinfects cells is the viral titer.

As used herein, the terms “treat”, “treatment” and “treating” refer toboth therapeutic and prophylactic treatments. For example, therapeutictreatments includes the reduction or amelioration of the progression,severity and/or duration of influenza viruses mediated conditions, orthe amelioration of one or more symptoms (specifically, one or morediscernible symptoms) of influenza viruses mediated conditions,resulting from the administration of one or more therapies (e.g., one ormore therapeutic agents such as a compound or composition of theinvention). In specific embodiments, the therapeutic treatment includesthe amelioration of at least one measurable physical parameter of aninfluenza virus mediated condition. In other embodiments the therapeutictreatment includes the inhibition of the progression of an influenzavirus mediated condition, either physically by, e.g., stabilization of adiscernible symptom, physiologically by, e.g., stabilization of aphysical parameter, or both. In other embodiments the therapeutictreatment includes the reduction or stabilization of influenza virusesmediated infections. Antiviral drugs can be used in the communitysetting to treat people who already have influenza to reduce theseverity of symptoms and reduce the number of days that they are sick.

The term “chemotherapy” refers to the use of medications, e.g. smallmolecule drugs (rather than “vaccines”) for treating a disorder ordisease.

The terms “prophylaxis” or “prophylactic use” and “prophylactictreatment” as used herein, refer to any medical or public healthprocedure whose purpose is to prevent, rather than treat or cure adisease. As used herein, the terms “prevent”, “prevention” and“preventing” refer to the reduction in the risk of acquiring ordeveloping a given condition, or the reduction or inhibition of therecurrence or said condition in a subject who is not ill, but who hasbeen or may be near a person with the disease. The term“chemoprophylaxis” refers to the use of medications, e.g. small moleculedrugs (rather than “vaccines”) for the prevention of a disorder ordisease.

As used herein, prophylactic use includes the use in situations in whichan outbreak has been detected, to prevent contagion or spread of theinfection in places where a lot of people that are at high risk ofserious influenza complications live in close contact with each other(e.g. in a hospital ward, daycare center, prison, nursing home, etc). Italso includes the use among populations who require protection from theinfluenza but who either do not get protection after vaccination (e.g.due to weak immunse system), or when the vaccine is unavailable to them,or when they cannot get the vaccine because of side effects. It alsoincludes use during the two weeks following vaccination, since duringthat time the vaccine is still ineffective. Prophylactic use may alsoinclude treating a person who is not ill with the influenza or notconsidered at high risk for complications, in order to reduce thechances of getting infected with the influenza and passing it on to ahigh-risk person in close contact with him (for instance, healthcareworkers, nursing home workers, etc).

According to the US CDC, an influenza “outbreak” is defined as a suddenincrease of acute febrile respiratory illness (AFRI) occurring within a48 to 72 hour period, in a group of people who are in close proximity toeach other (e.g. in the same area of an assisted living facility, in thesame household, etc) over the normal background rate or when any subjectin the population being analyzed tests positive for influenza. One caseof confirmed influenza by any testing method is considered an outbreak.

A “cluster” is defined as a group of three or more cases of AFRIoccurring within a 48 to 72 hour period, in a group of people who are inclose proximity to each other (e.g. in the same area of an assistedliving facility, in the same household, etc).

As used herein, the “index case”, “primary case” or “patient zero” isthe initial patient in the population sample of an epidemiologicalinvestigation. When used in general to refer to such patients inepidemiological investigations, the term is not capitalized. When theterm is used to refer to a specific person in place of that person'sname within a report on a specific investigation, the term iscapitalized as Patient Zero. Often scientists search for the index caseto determine how the disease spread and what reservoir holds the diseasein between outbreaks. Note that the index case is the first patient thatindicates the existence of an outbreak. Earlier cases may be found andare labeled primary, secondary, tertiary, etc.

In one embodiment, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, having apredisposition to complications resulting from infection by an influenzavirus. The term “pre-emptive” as used herein as for example inpre-emptive use, “pre-emptively”, etc, is the prophylactic use insituations in which an “index case” or an “outbreak” has been confirmed,in order to prevent the spread of infection in the rest of the communityor population group.

In another embodiment, the methods of the invention are applied as a“pre-emptive” measure to members of a community or population group,specifically humans, in order to prevent the spread of infection.

As used herein, an “effective amount” refers to an amount sufficient toelicit the desired biological response. In the present invention thedesired biological response is to inhibit the replication of influenzavirus, to reduce the amount of influenza viruses or to reduce orameliorate the severity, duration, progression, or onset of a influenzavirus infection, prevent the advancement of an influenza virusesinfection, prevent the recurrence, development, onset or progression ofa symptom associated with an influenza virus infection, or enhance orimprove the prophylactic or therapeutic effect(s) of another therapyused against influenza infections. The precise amount of compoundadministered to a subject will depend on the mode of administration, thetype and severity of the infection and on the characteristics of thesubject, such as general health, age, sex, body weight and tolerance todrugs. The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. When co-administered with otheranti viral agents, e.g., when co-administered with an anti-influenzamedication, an “effective amount” of the second agent will depend on thetype of drug used. Suitable dosages are known for approved agents andcan be adjusted by the skilled artisan according to the condition of thesubject, the type of condition(s) being treated and the amount of acompound described herein being used. In cases where no amount isexpressly noted, an effective amount should be assumed. For example,compounds described herein can be administered to a subject in a dosagerange from between approximately 0.01 to 100 mg/kg body weight/day fortherapeutic or prophylactic treatment.

Generally, dosage regimens can be selected in accordance with a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the renal andhepatic function of the subject; and the particular compound or saltthereof employed, the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The skilled artisan canreadily determine and prescribe the effective amount of the compoundsdescribed herein required to treat, to prevent, inhibit (fully orpartially) or arrest the progress of the disease.

Dosages of the compounds described herein can range from between about0.01 to about 100 mg/kg body weight/day, about 0.01 to about 50 mg/kgbody weight/day, about 0.1 to about 50 mg/kg body weight/day, or about 1to about 25 mg/kg body weight/day. It is understood that the totalamount per day can be administered in a single dose or can beadministered in multiple dosing, such as twice a day (e.g., every 12hours), tree times a day (e.g., every 8 hours), or four times a day(e.g., every 6 hours).

For therapeutic treatment, the compounds described herein can beadministered to a patient within, for example, 48 hours (or within 40hours, or less than 2 days, or less than 1.5 days, or within 24 hours)of onset of symptoms (e.g., nasal congestion, sore throat, cough, aches,fatigue, headaches, and chills/sweats). The therapeutic treatment canlast for any suitable duration, for example, for 5 days, 7 days, 10days, 14 days, etc. For prophylactic treatment during a communityoutbreak, the compounds described herein can be administered to apatient within, for example, 2 days of onset of symptoms in the indexcase, and can be continued for any suitable duration, for example, for 7days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

Various types of administration methods can be employed in theinvention, and are described in detail below under the section entitled“Administration Methods.”

Combination Therapy

An effective amount can be achieved in the method or pharmaceuticalcomposition of the invention employing a compound of the invention(including a pharmaceutically acceptable salt or solvate (e.g.,hydrate)) alone or in combination with an additional suitabletherapeutic agent, for example, an antiviral agent or a vaccine. When“combination therapy” is employed, an effective amount can be achievedusing a first amount of a compound of the invention and a second amountof an additional suitable therapeutic agent (e.g. an antiviral agent orvaccine).

In another embodiment of this invention, a compound of the invention andthe additional therapeutic agent, are each administered in an effectiveamount (i.e., each in an amount which would be therapeutically effectiveif administered alone). In another embodiment, a compound of theinvention and the additional therapeutic agent, are each administered inan amount which alone does not provide a therapeutic effect (asub-therapeutic dose). In yet another embodiment, a compound of theinvention can be administered in an effective amount, while theadditional therapeutic agent is administered in a sub-therapeutic dose.In still another embodiment, a compound of the invention can beadministered in a sub-therapeutic dose, while the additional therapeuticagent, for example, a suitable cancer-therapeutic agent is administeredin an effective amount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a subject.

Coadministration encompasses administration of the first and secondamounts of the compounds of the coadministration in an essentiallysimultaneous manner, such as in a single pharmaceutical composition, forexample, capsule or tablet having a fixed ratio of first and secondamounts, or in multiple, separate capsules or tablets for each. Inaddition, such coadministration also encompasses use of each compound ina sequential manner in either order.

In one embodiment, the present invention is directed to methods ofcombination therapy for inhibiting Flu viruses replication in biologicalsamples or patients, or for treating or preventing Influenza virusinfections in patients using the compounds or pharmaceuticalcompositions of the invention. Accordingly, pharmaceutical compositionsof the invention also include those comprising an inhibitor of Flu virusreplication of this invention in combination with an anti-viral compoundexhibiting anti-Influenza virus activity.

Methods of use of the compounds and compositions of the invention alsoinclude combination of chemotherapy with a compound or composition ofthe invention, or with a combination of a compound or composition ofthis invention with another anti-viral agent and vaccination with a Fluvaccine.

When co-administration involves the separate administration of the firstamount of a compound of the invention and a second amount of anadditional therapeutic agent, the compounds are administeredsufficiently close in time to have the desired therapeutic effect. Forexample, the period of time between each administration which can resultin the desired therapeutic effect, can range from minutes to hours andcan be determined taking into account the properties of each compoundsuch as potency, solubility, bioavailability, plasma half-life andkinetic profile. For example, a compound of the invention and the secondtherapeutic agent can be administered in any order within about 24 hoursof each other, within about 16 hours of each other, within about 8 hoursof each other, within about 4 hours of each other, within about 1 hourof each other or within about 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeuticagent such as a compound of the invention) can be administered prior to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksbefore), concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapy (e.g., a prophylactic or therapeuticagent such as an anti-cancer agent) to a subject.

It is understood that the method of co-administration of a first amountof a compound of the invention and a second amount of an additionaltherapeutic agent can result in an enhanced or synergistic therapeuticeffect, wherein the combined effect is greater than the additive effectthat would result from separate administration of the first amount of acompound of the invention and the second amount of an additionaltherapeutic agent.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapy (e.g., a prophylactic ortherapeutic agent), which is more effective than the additive effects ofthe therapies. A synergistic effect of a combination of therapies (e.g.,a combination of prophylactic or therapeutic agents) can permit the useof lower dosages of one or more of the therapies and/or less frequentadministration of said therapies to a subject. The ability to utilizelower dosages of a therapy (e.g., a prophylactic or therapeutic agent)and/or to administer said therapy less frequently can reduce thetoxicity associated with the administration of said therapy to a subjectwithout reducing the efficacy of said therapy in the prevention,management or treatment of a disorder. In addition, a synergistic effectcan result in improved efficacy of agents in the prevention, managementor treatment of a disorder. Finally, a synergistic effect of acombination of therapies (e.g., a combination of prophylactic ortherapeutic agents) may avoid or reduce adverse or unwanted side effectsassociated with the use of either therapy alone.

When the combination therapy using the compounds of the presentinvention is in combination with a Flu vaccine, both therapeutic agentscan be administered so that the period of time between eachadministration can be longer (e.g. days, weeks or months).

The presence of a synergistic effect can be determined using suitablemethods for assessing drug interaction. Suitable methods include, forexample, the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loeweadditivity (Loewe, S, and Muischnek, H., Arch. Exp. Pathol Pharmacol.114: 313-326 (1926)) and the median-effect equation (Chou, T. C. andTalalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equationreferred to above can be applied with experimental data to generate acorresponding graph to aid in assessing the effects of the drugcombination. The corresponding graphs associated with the equationsreferred to above are the concentration-effect curve, isobologram curveand combination index curve, respectively.

Specific examples that can be co-administered with a compound describedherein include neuraminidase inhibitors, such as oseltamivir (Tamiflu®)and Zanamivir (Rlenza®), viral ion channel (M2 protein) blockers, suchas amantadine (Symmetrel®) and rimantadine (Flumadine®), and antiviraldrugs described in WO 2003/015798, including T-705 under development byToyama Chemical of Japan. (See also Ruruta et al., Antiviral Reasearch,82: 95-102 (2009), “T-705 (flavipiravir) and related compounds: Novelbroad-spectrum inhibitors of RNA viral infections.”) In someembodiments, the compounds described herein can be co-administered witha traditional influenza vaccine. In some embodiments, the compoundsdescribed herein can be co-administered with Zanamivir. In someembodiments, the compounds described herein can be co-administered withoseltamivir. In some embodiments, the compounds described herein can beco-administered with T-705.Pharmaceutical Compositions

The compounds described herein can be formulated into pharmaceuticalcompositions that further comprise a pharmaceutically acceptablecarrier, diluent, adjuvant or vehicle. In one embodiment, the presentinvention relates to a pharmaceutical composition comprising a compoundof the invention described above, and a pharmaceutically acceptablecarrier, diluent, adjuvant or vehicle. In one embodiment, the presentinvention is a pharmaceutical composition comprising an effective amountof a compound of the present invention or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier, diluent,adjuvant or vehicle. Pharmaceutically acceptable carriers include, forexample, pharmaceutical diluents, excipients or carriers suitablyselected with respect to the intended form of administration, andconsistent with conventional pharmaceutical practices.

An “effective amount” includes a “therapeutically effective amount” anda “prophylactically effective amount”. The term “therapeuticallyeffective amount” refers to an amount effective in treating and/orameliorating an influenza virus infection in a patient infected withinfluenza. The term “prophylactically effective amount” refers to anamount effective in preventing and/or substantially lessening thechances or the size of influenza virus infection outbreak. Specificexamples of effective amounts are described above in the sectionentitled Uses of Disclosed Compounds.

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compounds.The pharmaceutically acceptable carriers should be biocompatible, e.g.,non-toxic, non-inflammatory, non-immunogenic or devoid of otherundesired reactions or side-effects upon the administration to asubject. Standard pharmaceutical formulation techniques can be employed.

The pharmaceutically acceptable carrier, adjuvant, or vehicle, as usedherein, includes any and all solvents, diluents, or other liquidvehicle, dispersion or suspension aids, surface active agents, isotonicagents, thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W.Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds describedherein, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. As used herein,the phrase “side effects” encompasses unwanted and adverse effects of atherapy (e.g., a prophylactic or therapeutic agent). Side effects arealways unwanted, but unwanted effects are not necessarily adverse. Anadverse effect from a therapy (e.g., prophylactic or therapeutic agent)might be harmful or uncomfortable or risky. Side effects include, butare not limited to fever, chills, lethargy, gastrointestinal toxicities(including gastric and intestinal ulcerations and erosions), nausea,vomiting, neurotoxicities, nephrotoxicities, renal toxicities (includingsuch conditions as papillary necrosis and chronic interstitialnephritis), hepatic toxicities (including elevated serum liver enzymelevels), myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins (such as humanserum albumin), buffer substances (such as twin 80, phosphates, glycine,sorbic acid, or potassium sorbate), partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes (such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, or zinc salts), colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, methylcellulose,hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucoseand sucrose; starches such as corn starch and potato starch; celluloseand its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as cocoa butter and suppository waxes; oils suchas peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil;corn oil and soybean oil; glycols; such a propylene glycol orpolyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Administration Methods

The compounds and pharmaceutically acceptable compositions describedabove can be administered to humans and other animals orally, rectally,parenterally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments, or drops), bucally, as an oral ornasal spray, or the like, depending on the severity of the infectionbeing treated.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound described herein, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are specificallysuppositories which can be prepared by mixing the compounds describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compositions described herein may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes, but is not limited to, subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Specifically, the compositions areadministered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions described herein may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation.

The pharmaceutical compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include, but arenot limited to, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. For oral administration ina capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions described herein may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter, beeswaxand polyethylene glycols.

The pharmaceutical compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,specifically, as solutions in isotonic, pH adjusted sterile saline,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions may also be administered by nasalaerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents.

The compounds for use in the methods of the invention can be formulatedin unit dosage form. The term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosage for subjects undergoingtreatment, with each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect,optionally in association with a suitable pharmaceutical carrier. Theunit dosage form can be for a single daily dose or one of multiple dailydoses (e.g., about 1 to 4 or more times per day). When multiple dailydoses are used, the unit dosage form can be the same or different foreach dose.

EXEMPLIFICATION Example 1 Synthesis of Compounds of the Invention

The compounds disclosed herein can be prepared by any suitable methodknown in the art, for example, WO 2005/095400, WO 2007/084557, WO2010/011768, WO 2010/011756, WP 2010/011772, WO 2009/073300, andPCT/US2010/038988 filed on Jun. 17, 2010. For example, the compoundsshown in Table 1 and FIG. 1 can be prepared by any suitable method knownin the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768,WO 2010/011756, WP 2010/011772, WO 2009/073300, and PCT/US2010/038988,and by the exemplary syntheses described below. Generally, the compoundsof the invention can be prepared as shown in those syntheses optionallywith any desired appropriate modification.

Methodology for Synthesis and Characterization of Compounds

Syntheses of certain exemplary compounds of the invention are describedbelow. NMR and Mass Spectroscopy data of certain specific compounds aresummarized in Table 1. As used herein the term RT (min) refers to theLCMS retention time, in minutes, associated with the compound.

Preparation of Compound 1

Formation of(R)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-4,4-dimethylpentanoicacid (3a)

To a solution of5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,1a, (0.100 g, 0.215 mmol: prepared in a similar manner as describedbelow for Compound 25a in scheme 4) and(R)-3-amino-4,4-dimethylpentanoic acid, 2a, (0.031 g, 0.215 mmol) intetrahydrofuran (1.66 mL) was added freshly ground Na₂CO₃ (0.068 g,0.645 mmol) followed by acetonitrile (0.331 mL). The reaction mixturewas heated to 135° C. for 30 minutes in a microwave reactor. Thereaction mixture was slowly poured into 75 mL of 1N HCl. The pH of finalsolution was adjusted to 1. The aqueous was extracted with EtOAc (3×5mL), washed with brine, dried over Na₂SO₄ and filtered to obtain a crudesolid residue. The crude residue was purified via silica gelchromatography (0-10% MeOH—CH₂Cl₂ gradient) afforded 78 mg of thedesired product 3a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, RT=3.9 minutes (M+H) 546.22.

(R)-3-(2-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-4,4-dimethylpentanoicacid (1)

To a cold (0° C.) solution of(R)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-4,4-dimethylpentanoicacid, 3a, (0.08 g, 0.14 mmol) in MeOH (2.6 mL) was added sodiummethanolate (2.91 mL of 25% w/v, 13.46 mmol). The reaction was stirredat room temperature for 30 min and then quenched by dilution intoaqueous saturated ammonium chloride solution. The MeOH was evaporated invacuo and the resulting aqueous phase diluted with EtOAc, then extractedwith EtOAc (3×). The organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. Recrystallization from MeOH provided 52 mg of thedesired product 1 as a white powder: ¹H NMR (d6-DMSO) δ 12.25 (s, 1H):12.0 (bs, 1H): 8.8 (s, 1H): 8.3 (s, 1H): 8.25 (s, 1H); 8.1 (s, 1H): 7.45(d, 1H); 4.75 (t, 1H); 2.5 (m, 2H), 1.0 (s, 9H); LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, RT=2.06 minutes (M+H) 392.21.

Preparation of Compounds 2, 43, 89 and 90

Formation of (R)-1-methoxy-4,4-dimethyl-1-oxopentan-3-aminium chloride(5a)

(R)-3-amino-4,4-dimethylpentanoic acid, 2a, was dissolved in methanol(1.4 L). The solution was cooled in an ice bath and acetyl chloride(67.0 mL, 947.0 mmol) was added dropwise (maintaining the temperaturebelow 10° C.). The reaction mixture was heated to 65° C. and stirred atthat temperature for 3 h. The reaction mixture was cooled to roomtemperature and then flushed with toluene to remove volatiles. The crudematerial was used without further purification: ¹H NMR (400 MHz,MeOH-d₄) δ 3.75 (s, 3H), 3.41 (t, 1H), 2.88 (dd, 1H), 2.64-2.46 (m, 1H),1.04 (s, 9H).

Formation of (R)-methyl3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate (6a)

(R)-1-methoxy-4,4-dimethyl-1-oxopentan-3-aminium chloride, 5a, (37 g,189 mmol) was dissolved in a mixture of tetrahydrofuran (667 mL) andEtOH (74 mL). The solution was cooled in an ice bath.2,4-dichloro-5-fluoro-pyrimidine (35 g, 208 mmol) was added, followed bythe dropwise addition of triethylamine (85 mL, 606 mmol). The reactionmixture was heated at 55° C. for 17 h. The reaction mixture was thencooled to room temperature after which water (625 mL) anddichloromethane (625 mL) were added. The phases were separated and theaqueous layer was washed with dichloromethane (625 mL). The organiclayers were combined and washed with brine. The solvents were removedand the residue was purified on silica gel (EtOAc/Hexanes): LCMSGradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=3.10 minutes (M+H)291.02.

Formation of (R)-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate(8a)

A 2-MeTHF (253 mL)/water (56 mL) solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (24.3 g, 58.3 mmol), methyl (R)-methyl3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoate, 6a,(14.1 g, 48.6 mmol) and K₃PO₄ (30.9 g, 146 mmol) was purged withnitrogen for 0.75 h. XPhos (2.8 g, 5.8 mmol) and Pd₂(dba)₃ (1.1 g, 1.2mmol) were added and the reaction mixture was stirred at 115° C. in asealed tube for 2 h. The reaction mixture was cooled and the aqueousphase was removed. The organic phase was filtered through a pad ofCelite and the mixture was concentrated to dryness. The residue waspurified on silica gel (EA/Hex) to provide the desired product, 8a,(23.2 g): LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN,RT=2.18 minutes (M+H) 245.28.

Formation of (R)-methyl3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate(9a)

To a solution of (R)-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate,8a, (21 g, 39 mmol) in acetonitrile (157 mL) was added 4M HCl in dioxane(174 mL). The reaction mixture was heated to 65° C. for 4 h. Thesolution was cooled to room temperature and the solvents were removedunder reduced pressure. The mixture was flushed with acetonitrile afterwhich dichloromethane (100 mL), sat. aqueous NaHCO₃ (355 mL) and ethylacetate (400 mL) were added. The phases were separated and the aqueouslayer washed with ethyl acetate (500 mL). The organic layers werecombined, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting residue was purified on silica gel (EtOAc/Hexanes) to providethe desired product, 9a, (12.1 g): LCMS Gradient 10-90%, 0.1% formicacid, 5 min, C18/ACN, RT=2.26 minutes (M+H) 391.05.

Formation(R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (2)

(R)-Methyl3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate,9a, (18.4 g, 47.1 mmol) was dissolved in tetrahydrofuran (275 mL) andaqueous 1M LiOH (141 mL) was added. The mixture was heated to 50° C. for3.5 h. The reaction mixture was cooled to room temperature and 180 mL ofwater was added. The tetrahydrofuran was removed under reduced pressureand the residue was then flushed twice with hexanes. Diethylether (60mL) was added and the layers separated. The pH of the aqueous layer wasadjusted to 6 with 1N HCl. Ethyl acetate (540 mL) was added, the layerswere separated and the aqueous layer was extracted with ethyl acetate(720 mL), then again with ethyl acetate (300 mL). The organic layerswere combined, washed with brine (100 mL) and dried (Na₂SO₄). Thesolvents were removed while flushing with heptanes to provide thedesired product, 2, (17.5 g): ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H),12.03 (s, 1H), 8.68-8.52 (m, 1H), 8.27 (s, 1H), 8.19 (d, J=2.5 Hz, 1H),8.13 (d, J=4.0 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 4.83 (t, J=9.3 Hz, 1H),2.71-2.51 (m, 2H), 0.97 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid,5 min, C18/ACN, RT=1.96 minutes (M+H) 377.02.

The following analog was prepared in a similar fashion as the proceduredescribed above for Compound 2:

(R)-3-((5-fluoro-2-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (43)

¹H NMR (300 MHz, CDCl₃) δ 11.16 (s, 1H), 8.70 (s, 1H), 8.04 (d, J=3.2Hz, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 5.02 (d, J=8.1 Hz, 1H), 4.80 (t,J=9.6 Hz, 1H), 2.81 (d, J=9.9 Hz, 1H), 2.34 (t, J=11.3 Hz, 1H), 1.14 (s,9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=2.49 minutes (M+H) 426.47.

(R)-3-((5-fluoro-2-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (90)

¹H NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 8.43 (d, J=14.1 Hz, 2H), 8.23(s, 1H), 4.96 (s, 2H), 2.88-2.55 (m, 4H), 2.45 (s, 3H), 1.00 (s, 9H);LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=1.8 minutes (M+H) 372.5.

(R)-3-((2-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (89)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=2.1 minutes (M+H) 383.38.

(S)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (4)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=1.93 minutes (M+H) 376.21.

(S)-3-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (3)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=2.06 minutes (M+H) 392.21.

Preparation of Compound 69

Formation of(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol(14a)

To a mixture of (2S)-2-amino-3,3-dimethyl-butan-1-ol (5.0 g, 42.7 mmol)and 2,4-dichloro-5-fluoro-pyrimidine (5.7 g, 42.7 mmol) in DMF (50 mL)was added triethylamine (7.1 mL, 51.2 mmol). After 90 minutes, thereaction was diluted into aqueous saturated NH₄Cl solution and extractedtwice with EtOAc. The combined organic phases were washed twice withbrine, dried (MgSO₄), filtered and concentrated in vacuo. The cruderesidue was purified via silica gel chromatography (0-10% MeOH/CH₂Cl₂gradient) to afford 6.7 g of the desired product, 1, as a sticky solid:LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.48minutes (M+H) 248.32.

Formation of(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal (15a)

To a cold (−78° C.) solution of oxalyl chloride (1.06 mL, 12.11 mmol) indichloromethane (10 mL) was added dimethyl sulfoxide (1.43 mL, 20.18mmol) dropwise. After stirring the mixture for 10 minutes at −78° C., asuspension of(2S)-2-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3,3-dimethyl-butan-1-ol,14a, (1.0 g, 4.04 mmol) in dichloromethane (10 mL) was added. Thereaction mixture was stirred for 30 minutes at −78° C. and triethylamine(3.38 mL, 24.22 mmol) was added. The mixture was slowly warmed to 0° C.over 2 hours. The mixture was diluted into aqueous saturated NaHCO₃solution and extracted twice with EtOAc. The combined organic phaseswere dried (MgSO₄), filtered and concentrated in vacuo. The cruderesidue was purified via silica gel chromatography (0-15% EtOAc/CH₂Cl₂gradient) to afford 680 mg of the desired product as a white solid.

Formation of (R,E)-diisopropyl(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate(16a)

To a cold (0° C.) suspension of sodium hydride (0.163 g, 7.083 mmol) inTHF (8.0 mL) was added2-(diisopropoxyphosphorylmethyl(isopropoxy)phosphoryl)-oxypropane (1.220g, 3.542 mmol). After 15 minutes, a solution of(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal, 15a,(0.580 g, 2.361 mmol) in THF (4 mL) was added dropwise. The reactionmixture was slowly warmed to room temperature over 1 hour. The mixturewas diluted into aqueous saturated NH₄Cl solution and extracted withEtOAc. The organic phase was dried (MgSO₄), filtered and concentrated invacuo. The resulting crude residue was purified via silica gelchromatography (10-50% EtOAc/CH₂Cl₂ gradient) to afford 810 mg of thedesired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, RT=3.28 minutes (M+H) 408.36.

Formation of (R,E)-diisopropyl(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate(17a)

To a solution of (R,E)-diisopropyl(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate,16a, (0.81 g, 1.99 mmol) and5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (1.24 g, 3.00 mmol) in 2-Me-THF (16 mL) was added K₃PO₄ (1.27 g,3.00 mmol) and water (4 mL). The biphasic mixture was degassed under astream of nitrogen for 15 minutes. Then, X-Phos (0.11 g, 0.24 mmol) andPd₂(dba)₃ (0.06 g, 0.06 mmol) was added to the mixture. After degassingwith nitrogen for an additional 5 minutes, the vessel was sealed andheated at 100° C. for 2 hours. The mixture was cooled to roomtemperature and diluted with EtOAc, filtered through celite. Thefiltrate was washed with brine, dried (MgSO₄), filtered and concentratedin vacuo. The crude residue was purified via silica gel chromatography(0-50% EtOAc/CH₂Cl₂ gradient) to afford 1.123 g of the desired product:¹H NMR (400 MHz, d6-DMSO) δ 8.55-8.42 (m, 3H), 8.31 (d, J=3.7 Hz, 1H),8.06 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.9 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H),6.80 (ddd, J=22.2, 17.1, 6.9 Hz, 1H), 5.99 (dd, J=20.3, 17.1 Hz, 1H),4.95 (t, J=7.6 Hz, 1H), 4.51-4.32 (m, 2H), 2.35 (s, 3H), 1.19-1.14 (m,6H), 1.11 (dd, J=6.0, 4.4 Hz, 6H), 1.02 (s, 9H).); LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, RT=4.06 minutes (M+H) 662.35.

Formation of (R,E)-diisopropyl(3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate(18a)

To a solution of (R,E)-diisopropyl(3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate,17a, (1.0 g, 1.51 mmol) in methanol (30 mL) was added sodium methoxide(8.2 mL of 25% wt solution in MeOH). After 3 minutes, the mixture wasdiluted into aqueous saturated NH₄Cl solution and extracted twice withEtOAc. The combined organic phases were dried (MgSO₄), filtered andconcentrated in vacuo. The crude residue was purified via silica gelchromatography (0-15% MeOH/CH₂Cl₂ gradient) to afford 724 mg of thedesired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, RT=2.76 minutes (M+H) 508.13.

Formation of(R)-diisopropyl-(3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentyl)phosphonate(19a)

To a solution of (R,E)-diisopropyl(3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-1-en-1-yl)phosphonate,18a, (0.36 g, 0.71 mmol) in MeOH (7 mL) was added Pd on Carbon (10%,wet, Degussa, 0.07 g, 0.07 mmol). The reaction mixture was stirred in aParr hydrogenation flask under 50 psi of hydrogen overnight. The mixturewas diluted with EtOAc and filtered through celite. The filtrate wasconcentrated in vacuo to give the desired product as dark gray solid: ¹HNMR (400 MHz, d6-DMSO) δ 12.28 (s, 1H), 8.46 (dd, J=9.9, 2.7 Hz, 1H),8.30-8.21 (m, 2H), 8.15 (d, J=3.9 Hz, 1H), 7.29 (d, J=9.5 Hz, 1H), 4.51(dt, J=12.3, 6.2 Hz, 2H), 4.37 (t, J=9.8 Hz, 1H), 1.95-1.60 (m, 3H),1.59-1.35 (m, 1H), 1.24-1.09 (m, 12H), 0.99 (s, 9H); LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.46 minutes (M+H)510.56.

Formation of(R)-(3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentyl)phosphonicacid (69)

To a solution of(R)-diisopropyl-(3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentyl)phosphonate,19a, (0.16 g, 0.32 mmol) in dichloromethane (8 mL) was addediodotrimethylsilane (0.45 mL, 3.18 mmol). The reaction mixture wasstirred at room temperature. After 1 hour, LCMS showed the reaction tobe incomplete. An additional 0.90 mL of iodotrimethylsilane (0.64 mmol)was added to the reaction mixture. After 5 hours, the mixture wasconcentrated in vacuo and the resulting residue was purified viapreparatory HPLC (CH₃CN/1% aqueous TFA) to afford 8 mg of phosphonicacid, 69, and 34 mg of phosphonate, 21a.

Spectral data for phosphonic acid, 69: ¹H NMR (300 MHz, MeOD) δ8.59-8.39 (m, 2H), 8.32 (t, J=5.3 Hz, 2H), 4.59 (d, J=9.5 Hz, 2H), 2.21(s, 1H), 1.79 (dddd, J=28.6, 23.0, 13.2, 6.9 Hz, 3H), 1.11 (d, J=9.5 Hz,9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.81minutes (M+H) 426.09.

Spectral data for phosphonate 21a: ¹H NMR (300 MHz, MeOD) δ 8.57-8.41(m, 2H), 8.32 (d, J=5.6 Hz, 2H), 4.73-4.41 (m, 2H), 2.25 (d, J=25.7 Hz,1H), 2.06-1.43 (m, 3H), 1.32-1.20 (m, 6H), 1.11 (d, J=11.2 Hz, 9H); LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.06 minutes(M+H) 468.13.

Preparation of Compounds 16 and 17

Formation of 3-bromo-5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine(22a)

3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 23.3 mmol) wasdissolved in DMF (37.5 mL) and cooled to 0° C. Sodium hydride (1.5 g,37.2 mmol) was added and the reaction mixture was stirred for 10 minutesand then treated with tosyl chloride (6.6 g, 34.9 mmol). The mixture wasstirred for 30 minutes at 0° C. and then at room temperature for another90 minutes. The reaction mixture was poured into water (100 mL) and theresulting solid was collected, washed with water and hexanes three timesand dried in vacuo to afford 8.26 g of3-bromo-5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a: ¹H NMR(300 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.31 (s, 1H), 8.01 (d, J=8.3 Hz, 2H),7.92 (dd, J=8.4, 2.7 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 2.35 (s, 3H).

Formation of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(7a)

3-bromo-5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a, (4.0 g,10.8 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(8.3 g, 32.5 mmol) and potassium acetate (3.2 g, 32.5 mmol) were takenin dioxane (40 mL) containing a few drops of water. After purging withnitrogen for 30 minutes, PdCl₂(dppf) (0.8 g, 1.1 mmol) was added.Nitrogen purging was continued for an additional 40 minutes, then thereaction mixture was heated to reflux overnight. After cooling down, themixture was filtered through Florisil (60 g), washed withdichloromethane (220 mL) and concentrated in vacuo to provide a brownoil. The crude product was taken into hexane (40 mL) and TBME (14 mL)and heated to reflux. After cooling to room temperature, the resultingsuspension was filtered to provide 2.6 g of the desired product as awhite solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.42 (dd, J=2.7, 1.4 Hz, 1H),8.14 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.85 (dd, J=8.6, 2.8 Hz, 1H), 7.44(d, J=8.3 Hz, 2H), 2.36 (s, 3H), 1.32 (s, 12H).

Formation of5-fluoro-3-(5-fluoro-4-methylsulfanyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine(24a)

2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (1.6 g, 9.0 mmol),5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (2.5 g, 6.0 mmol) and Na₂CO₃ (1.9 g, 18.0 mmol) were dissolved inDME (37.5 mL) and water (7.5 mL). The mixture was purged with nitrogenfor 20 minutes, treated with Pd(PPh₃)₄, purged with nitrogen for another20 minutes and heated to reflux overnight. After cooling to roomtemperature, water (35 mL) was added and the resulting suspension wasstirred for 30 minutes. The precipitate was collected by filtration,washed with water and acetonitrile and dried overnight at 50° C.,affording 2.3 g (88.5%) of the desired product as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 8.70-8.57 (m, 2H), 8.55-8.42 (m, 2H), 8.09 (d,J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

Formation of5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine(25a)

5-fluoro-3-(5-fluoro-4-methylsulfanyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,24a, (2.30 g, 5.32 mmol) was dissolved in dichloromethane (107 mL) andtreated portionwise with 3-chloroperbenzoic acid (1.19 g, 5.30 mmol),keeping the temperature below 20° C. After stirring for 2 hours, anotherportion of 3-chloroperbenzoic acid (0.18 g, 0.80 mmol) was added, andstirring was continued for another hour. A third portion of3-chloroperbenzoic acid (0.07 g, 0.05 mmol) was added and stirring wascontinued for 30 minutes. The reaction mixture was treated with anaqueous 15% K₂CO₃ solution (30 mL) and the layers were separated. Theorganic layer was washed with 15% K₂CO₃ and brine, dried (Na₂SO₄),filtered and concentrated in vacuo to afford 2.3 g (96%) of the desiredproduct as a yellow solid, which was used without further purification:¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 8.67(dd, J=9.1, 2.8 Hz, 1H), 8.53 (d, J=1.5 Hz, 1H), 8.11 (d, J=8.4 Hz, 2H),7.46 (d, J=8.2 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).

The following analog was prepared in a similar fashion as the proceduredescribed above for sulfoxide, 25a:

5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine(1a)

¹H NMR (300 MHz, d6-DMSO) δ 9.12 (d, J=1.3 Hz, 1H), 8.90 (d, J=2.4 Hz,1H), 8.68 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.46(d, J=8.4 Hz, 2H), 2.54-2.48 (m, 3H), 2.36 (s, 3H).

Formation of 2,2-dimethylbutanal (26a)

To a solution of 1,1-dimethylpropyl magnesium chloride (20.0 mL of 1 M,20.0 mmol) in ether (25 mL) was added N-methyl-N-phenyl formamide (5.26mL, 20.0 mmol) in one portion (exothermic). The yellow solution wasgently refluxed for two hours and stirred at room temperature for threehours. At the end of this period the Grignard complex was quenched bypouring onto 500 g of crushed ice and 20 ml. of concentrated sulfuricacid. The ether layer was separated and the aqueous phase extractedthree times with 50 mL portions of ether. The combined ether extractswere dried (MgSO₄) and concentrated in vacuo. The crude residue waspurified by short-path distillation to afford 1.0 g of pure2,2-dimethylbutanal as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 4.17(q, J=7.1 Hz, 2H), 3.03 (dd, J=10.9, 2.3 Hz, 1H), 2.53 (dd, J=15.3, 2.3Hz, 1H), 2.15 (dd, J=15.3, 10.9 Hz, 1H), 1.50-1.33 (m, 3H), 1.28 (dd,J=9.0, 5.3 Hz, 3H), 1.26-1.17 (m, 1H), 0.85 (d, J=5.8 Hz, 6H).

Formation of ethyl 3-amino-4,4-dimethylhexanoate (27a)

A mixture of 2,2-dimethylbutanal, 26a, (3.00 g, 26.75 mmol), malonicacid (2.08 g, 1.29 mL, 20.00 mmol), ammonium acetate (3.08 g, 40.00mmol) in ethanol (5 mL) was refluxed for three hours. The precipitatewas removed by filtration and washed with ethanol. The solution was usedwithout further purification.

Sulfuric acid (1.962 g, 1.066 mL, 20.00 mmol) was added to above ethanolsolution and the resulting mixture was heated to reflux for two hours.The solvent was removed under reduced pressure. Water (20 mL) and ether(10 mL) were added to the crude residue. The aqueous layer was separatedand washed with ether (10 mL). The organic layers were discarded. Theaqueous solution was neutralized with sodium hydroxide solution (6N) andsaturated sodium bicarbonate solution to basic, and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with water(10 mL), brine (10 mL), filtered, dried (MgSO₄), filtered andconcentrated in vacuo to give 0.5 g of the desired product as a lightyellow sticky oil, which turned into solid upon standing. The crudeproduct was used without further purification: ¹H NMR (400 MHz, CDCl₃) δ4.17 (q, J=7.1 Hz, 2H), 3.03 (dd, J=10.9, 2.3 Hz, 1H), 2.53 (dd, J=15.3,2.3 Hz, 1H), 2.15 (dd, J=15.3, 10.9 Hz, 1H), 1.50-1.33 (m, 3H), 1.28(dd, J=9.0, 5.3 Hz, 3H), 1.26-1.17 (m, 1H), 0.85 (d, J=5.8 Hz, 6H).

Formation of ethyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylhexanoate(28a)

To a suspension of ethyl 3-amino-4,4-dimethylhexanoate, 27a, (0.19 g.1.00 mmol) and5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine,25a, (0.54 g, 1.20 mmol) in THF (14.4 mL) was addedN,N-diisopropylethylamine (0.26 mL, 1.50 mmol). The mixture was refluxedat 80° C. overnight. After removing the solvents under reduced pressure,the crude product was purified by silica gel chromatography (0-50%EtOAc/Hexane gradient) to afford 155 mg of the desired product as alight yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.61 (dd, J=9.0, 2.9 Hz,1H), 8.56 (s, 1H), 8.33 (dd, J=2.7, 1.0 Hz, 1H), 8.11 (d, J=8.4 Hz, 2H),7.30 (d, J=8.2 Hz, 2H), 5.19 (dd, J=10.1, 2.2 Hz, 1H), 4.94 (td, J=10.0,3.7 Hz, 1H), 3.99 (dt, J=13.7, 6.8 Hz, 2H), 2.40 (s, 3H), 1.42 (dt,J=14.1, 6.9 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H), 1.01-0.94 (m, 8H); ¹⁹F NMR(282 MHz, CDCl₃) δ −130.39-133.75 (dd, J=9.0, 1.1 Hz, 1F), −158.56 (s,1F); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.18minutes (M+H) 572.07.

Formation of3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylhexanoicacid (16, 17)

To a solution of ethyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylhexanoate,28a, (0.16 g, 0.27 mmol) in THF (6 mL) was added LiOH (1.50 mL of 1 Msolution, 1.50 mmol). The reaction mixture was heated in a microwavereactor at 130° C. for thirty minutes. The reaction was quenched by theaddition of aqueous saturated NH₄Cl solution. The resulting whiteprecipitate was collected and washed with water, acetonitrile and ether.The combined organic phases were then concentrated in vacuo to give puredesired carboxylic acid as a solid. The solid was diluted withhydrochloric acid (2 mL of 1N solution) and lyophilized to give 110 mgof the desired product as a hydrochloride salt (light yellow powder): ¹HNMR (300 MHz, MeOD) δ 8.73 (d, J=9.5 Hz, 1H), 8.16 (s, 1H), 8.15-8.10(m, 1H), 7.93 (d, J=4.0 Hz, 1H), 5.02 (d, J=6.4 Hz, 1H), 3.75 (ddd,J=6.7, 4.2, 2.5 Hz, 3H), 2.66 (d, J=11.2 Hz, 1H), 2.45 (dd, J=14.0, 9.9Hz, 1H), 1.93-1.83 (m, 3H), 1.46 (d, J=7.5 Hz, 2H), 1.05-0.93 (m, 9H);¹⁹F NMR (282 MHz, MeOD) 6-139.17 (s, 1F), −160.86 (s, 1F); LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.04 minutes (M+H)390.23.

The racemic mixture was submitted to SFC chiral separation to give theindividual enantiomers, 16, and 17.

Preparation of Compounds 14 and 15

Formation of 1-methylcyclopentanecarbonitrile (31a)

To a cold (−78° C.) solution of LiHMDS (48.0 mL of 1 M solution intetrahydrofuran, 48.0 mmol) in tetrahydrofuran was added dropwise asolution of cyclopentanecarbonitrile (3.81 g, 40.0 mmol) intetrahydrofuran (10 mL) over a 5 minute period. After stirring at −78°C. for thirty minutes, methyl iodide (3.74 mL, 60.00 mmol) was added inone portion. The reaction was allowed to warm to room temperatureovernight. The solution was cooled to 0° C., ethyl acetate (50 mL) andaqueous saturated ammonium chloride solution (20 mL) was added.Additional water (10 mL) was added to dissolve the solid. The organiclayer was separated and washed with aqueous saturated ammonium chloride(20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL).The combined organic phases were washed with brine, dried (MgSO₄),filtered and concentrated in vacuo to give a 4.7 g of a yellow oil thatwas used without further purification: ¹H NMR (400 MHz, CDCl₃) δ2.04-1.93 (m, 2H), 1.77-1.65 (m, 2H), 1.66-1.55 (m, 2H), 1.54 (m, 2H),1.25 (s, 3H).

Formation of 1-methylcyclopentanecarbaldehyde (32a)

To a cold (−78° C.) solution of diisobutylaluminum hydride (100.0 mL of1 M solution, 100.0 mmol) in dichloromethane was added dropwise asolution of 1-methylcyclopentanecarbonitrile, 31a, (4.3 g, 40.0 mmol) indichloromethane (5 mL). The reaction was kept at −78° C. for thirtyminutes. The dry-ice bath was removed and methanol (1 mL) was added toquench the reaction. Potassium sodium tartrate solution (30 mL, 10%solution) was added and the mixture stirred vigorously. The organiclayer was separated and the aqueous layer was extracted withdichloromethane (3×20 mL). The combined organic phases were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo togive 3 g of a light yellow oil that was used without furtherpurification: ¹H NMR (400 MHz, CDCl₃) δ 2.04-1.93 (m, 2H), 1.77-1.65 (m,2H), 1.66-1.55 (m, 2H), 1.54 (m, 2H), 1.25 (s, 3H).

Formation of ethyl 3-amino-3-(1-methylcyclopentyl)propanoate (33a)

A mixture of 1-methylcyclopentanecarbaldehyde, 32a, (3.00 g, 26.75mmol), malonic acid (1.29 mL, 20.00 mmol) and ammonium acetate (3.08 g,40.00 mmol) in ethanol (5 mL) was refluxed for 12 hours. The precipitatewas removed by filtration and washed with ethanol. The filtrate was usedwithout further purification.

Sulfuric acid (1.07 mL, 20.00 mmol) was added to the above ethanolsolution and heated to reflux for 2 h. The solvent was removed underreduced pressure. The residue was diluted with water (20 mL) and ether(10 mL). The aqueous layer was separated and washed with ether (10 mL).The organic layers were discarded. The aqueous solution was neutralizedwith sodium hydroxide solution (6N) to basic, and extracted with ethylacetate (3×10 mL). The combined organic layers were washed with water(10 mL), brine (10 mL), filtered, dried (MgSO₄), filtered andconcentrated in vacuo to give 1.5 g of a light yellow sticky oil thatturned into solid upon standing. The crude product was used withoutfurther purification: ¹H NMR (400 MHz, CDCl₃) δ 4.25-4.14 (q, 2H), 3.40(bs, 2H), 3.20-3.09 (m, 1H), 2.48 (ddd, J=26.2, 16.0, 6.6 Hz, 2H),1.77-1.58 (m, 4H), 1.52 (m, 2H), 1.47-1.32 (m, 2H), 1.25 (m, 3H), 0.94(s, 3H).

Formation of ethyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclopentyl)propanoate(34a)

A suspension of ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a,(0.20 g, 1.00 mmol),5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine,25a (0.54 g, 1.20 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.50mmol) in THF (14.4 mL) was refluxed at 80° C. overnight. After removingthe solvent in vacuo, the crude product was purified by silica gelchromatography (0-50% EtOAc/Hexanes gradient) to afford 300 mg of thedesired product as a light yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.49(dd, J=9.0, 2.8 Hz, 1H), 8.46 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.02 (d,J=8.3 Hz, 2H), 7.99 (d, J=3.1 Hz, 1H), 7.20 (d, J=7.8 Hz, 2H), 5.23 (d,J=8.9 Hz, 1H), 4.80 (td, J=9.7, 3.6 Hz, 1H), 4.04 (q, J=7.1 Hz, 1H),3.91 (q, J=7.1 Hz, 2H), 2.73-2.58 (m, 1H), 2.44 (dd, J=14.7, 9.6 Hz,1H), 2.33-2.21 (m, 3H), 1.72-1.46 (m, 7H), 1.42-1.31 (m, 1H), 1.28 (t,J=6.1 Hz, 1H), 1.17 (dd, J=13.4, 6.2 Hz, 2H), 0.98 (t, J=7.1 Hz, 6H);LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=4.25minutes (M+H) 584.29.

Formation of ethyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclopentyl)propanoate(14, 15)

To a solution of ethyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclopentyl)propanoate,34a, (0.16 g, 0.27 mmol) in THF (6 mL) was added LiOH (1.50 mL of 1 Msolution, 1.50 mmol). The reaction mixture was irradiated in a microwavereactor for 30 minutes at 130° C. Aqueous saturated NH₄Cl solution wasadded to acidify the mixture. The resulting white precipitate wascollected and washed with water, acetonitrile and ether. The solid wasthen dried in vacuo to give pure desired acid. To the solid was addedhydrochloric acid (2 mL of 1N solution) and the mixture was lyophilizedto give 120 mg of the desired product as a hydrochloride salt (lightyellow powder): ¹H NMR (400 MHz, MeOD) δ 8.64 (d, J=9.3 Hz, 1H), 8.14(d, J=8.3 Hz, 2H), 7.97 (d, J=3.6 Hz, 1H), 4.99 (d, J=6.3 Hz, 1H), 3.37(s, 1H), 2.75 (dd, J=14.9, 3.6 Hz, 1H), 2.55 (dd, J=14.8, 9.7 Hz, 1H),1.83-1.57 (m, 6H), 1.54-1.42 (m, 1H), 1.37 (dd, J=11.9, 5.6 Hz, 1H),1.11 (d, J=19.2 Hz, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, RT=2.10 minutes (M+H) 401.94.

The racemic mixture of carboxylic acids was submitted to SFC chiralseparation to give the individual enantiomers, 14 and 15.

Preparation of Compounds 20 and 23

Formation of (R,E)-ethyl4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate(37a)

To a solution of(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal, 15a,(0.45 g, 1.84 mmol) in dichloromethane (9.0 mL) was added ethyl2-triphenylphosphoranylideneacetate (0.96 g, 2.75 mmol). After allowingthe reaction mixture to stir at room temperature overnight,approximately half of the solvent was removed under reduced pressure.The remaining crude mixture was purified by directly loading onto asilica gel column (0-100% EtOAc/hexanes) to afford 535 mg of the desiredproduct: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,RT=3.41 minutes (M+H) 316.32.

Formation of (R,E)-ethyl4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate(38a)

K₃PO₄ (1.078 g, 5.079 mmol) was dissolved in water (3.2 mL) and added toa solution of (R,E)-ethyl4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate,37a, (0.534 g, 1.693 mmol) in 2-methyl-THF (10.7 mL) and the mixture waspurged with nitrogen for 30 minutes.5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.775 g, 1.862 mmol) was added and the nitrogen purging wascontinued for an additional 15 min. X-Phos (0.048 g, 0.102 mmol) andPd₂(dba)₃ (0.031 g, 0.034 mmol) were added and the mixture was heated at80° C. overnight. After cooling to room temperature, the reactionmixture was diluted with water and extracted with EtOAc. The layers wereseparated and the organic phase was washed with brine, dried over MgSO₄,filtered and evaporated to dryness. The crude residue was dissolved in aminimum volume of dichloromethane and purified by silica gelchromatography (0-100% EtOAc/hexanes gradient) to afford 650 mg ofdesired product: ¹H NMR (400 MHz, CDCl₃) δ 8.57-8.38 (m, 2H), 8.30 (s,1H), 8.11 (dd, J=10.5, 5.5 Hz, 3H), 7.08 (dt, J=36.7, 18.3 Hz, 1H), 6.01(d, J=15.7 Hz, 1H), 5.11 (d, J=8.7 Hz, 1H), 4.97-4.77 (m, 1H), 4.19 (q,J=7.1 Hz, 2H), 2.39 (d, J=10.7 Hz, 3H), 1.27 (q, J=7.4 Hz, 4H), 1.10 (s,9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.99minutes (M+H) 570.01.

Formation of (R)-ethyl4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate(39a)

To a nitrogen purged flask charged with 10% Pd/C (0.033 g, 0.310 mmol)was added enough methanol to cover the catalyst. To this mixture wasadded a solution of (R,E)-ethyl4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate,38a, (0.330 g, 0.579 mmol) in MeOH. Note, a small amount of EtOAc wasadded to fully solubilize the starting material. The reaction mixturewas then stirred under 1 atmosphere of hydrogen for 3 hours. LCMS showspresence of significant amounts of starting material. The contents ofthe reaction mixture were transferred to a pressure vessel containing afresh source of palladium (0.033 g, 0.310 mmol). The reaction mixturewas stirred in a Parr hydrogenation flask under 46 psi of hydrogenovernight. The mixture was diluted with methanol and filtered throughcelite. The filtrate was concentrated in vacuo to afford 331 mg of thedesired product that was used without further purification: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.75 minutes(M+H) 572.35.

Formation of(R)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoicacid (20)

To a solution of (R)-ethyl4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate,39a, (0.30 g, 0.53 mmol) was in acetonitrile (5 mL) was added HCl (0.70mL of 4 M solution in dioxane, 2.80 mmol). The reaction mixture washeated at 60° C. for 3 hours and then heated to 80° C. for 6 hours todrive the reaction to completion. After cooling to room temperature, themixture was then stirred overnight. LCMS showed remaining startingmaterial. Fresh HCl (0.7 mL of 4 M solution in dioxane, 2.80 mmol) wasadded and the mixture was heated to 80° C. overnight. All volatiles wereremoved under reduced pressure and the residue was diluted with EtOAcand aqueous saturated NaHCO₃ solution. The layers were separated and theorganic phase was washed with brine, dried over MgSO₄, filtered andevaporated to dryness. The crude residue was purified by silica gelchromatography (0-100% EtOAc/hexanes gradient) to afford 144 mg of(R)-ethyl4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate,23, and 29 mg of(R)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexanoicacid, 20. Spectral data for 20: ¹H NMR (400 MHz, DMSO) δ 12.23 (s, 1H),11.93 (s, 1H), 8.48 (d, J=9.9 Hz, 1H), 8.33-8.07 (m, 3H), 7.18 (d, J=9.3Hz, 1H), 4.39 (t, J=10.2 Hz, 1H), 2.38-2.07 (m, 2H), 1.99-1.92 (m, 1H),1.80-1.64 (m, 1H), 1.00 (d, J=20.2 Hz, 9H); LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, RT=2.14 minutes (M+H) 390.06.

Preparation of Compound 59

Formation of(R,E)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoicacid (59)

Starting ethyl ester, 42a, was prepared in the same fashion as theenantiomeric ethyl ester, 38a, shown in Synthetic Scheme 7.

To a solution of (S,E)-ethyl4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate,42a, (0.064 g, 0.112 mmol) in dioxane (2 mL) was added LiOH (2 mL of 2Nsolution). After heating at 100° C. for 2 hours, the mixture wasacidified to pH 6 with 2N HCl. The aqueous phase was extracted withethyl acetate (3×), dried (MgSO4), filtered and concentrated in vacuo.The resulting residue was purified via preparatory HPLC (CH₃CN/H₂O— TFAmodifier) to afford 35 mg of the desired product as a TFA-salt: ¹H NMR(300 MHz, MeOD) δ 8.54 (s, 1H), 8.50-8.18 (m, 3H), 7.18 (dd, J=15.7, 7.1Hz, 1H), 6.08 (dd, J=15.7, 1.3 Hz, 1H), 5.21 (t, J=22.5 Hz, 1H), 1.12(s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,(M+H) 388.23.

Preparation of Compound 44

Formation of cyclobutanecarbaldehyde (45a)

To a stirred suspension of pyridinium chlorochromate (14.9 g, 69.1 mmol)in dichloromethane (150 mL) was added a solution of cyclobutylmethanol(4.0 g, 46.4 mmol) in dichloromethane (60 mL). The reaction mixtureturned black within a few minutes and was allowed to stir at roomtemperature for 1 hour. The mixture was diluted with diethyl ether (500mL) and filtered through a bed of florisil (100-200 mesh). The crudematerial was used without further purification. Note: the product isvolatile, the solvent was carried with the product onto the next step.

Formation of (E)-ethyl 3-cyclobutylacrylate (46a)

Ethyl 2-triphenylphosphoranylideneacetate (9.32 g, 26.74 mmol) was addedto a solution of cyclobutanecarbaldehyde, 45a, (1.50 g, 17.83 mmol) indichloromethane (30 mL). The reaction mixture was briefly purged withnitrogen and capped allowed to stir at room temperature overnight. Allvolatiles were removed at reduced pressure and the residue was dissolvedin Et₂O (100 mL) and hexanes (25 mL). The resulting pink precipitate wasfiltered off and discarded. The solvent was removed from the filtrate atreduced pressure. The crude product was purified via silica gelchromatography (0-20% EtOAc/Hexanes gradient) to afford 646 mg (23%) ofthe desired product: ¹H NMR (400 MHz, CDCl₃) δ 7.05 (dd, J=15.6, 6.8 Hz,1H), 5.73 (dd, J=15.6, 1.4 Hz, 1H), 4.29-4.09 (m, 2H), 3.20-2.98 (m,1H), 2.28-2.09 (m, 2H), 2.04-1.78 (m, 4H), 1.36-1.18 (m, 3H).

Formation of 2-benzyl-3-cyclobutylisoxazolidin-5-one (47a)

N-benzylhydroxylamine hydrochloride (0.77 g, 4.82 mmol) andtriethylamine (0.76 mL, 5.45 mmol) were successively added to a solutionof (E)-ethyl 3-cyclobutylacrylate, 46a, (0.65 g, 4.19 mmol) in drydichloromethane (23.5 mL). The reaction mixture was allowed to stir atroom temperature under an atmosphere of nitrogen for 3 days. The mixturewas diluted with 75 mL of water and the layers were separated. Theaqueous phase was reextracted twice more with dichloromethane (50 mL).The combined organic phases were dried over MgSO₄, filtered andevaporated to dryness. The residue was purified via silica gelchromatography (0-100% EtOAc/Hexanes gradient) to afford 834 mg (86%) ofthe desired product: ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.26 (m, 5H), 4.64(s, 1H), 3.82 (q, J=13.5 Hz, 2H), 3.37-3.18 (m, 1H), 2.80-2.52 (m, 2H),2.33 (dd, J=14.5, 5.1 Hz, 1H), 2.22-2.09 (m, 1H), 2.01-1.68 (m, 5H).

Formation of (+/−)-3-amino-3-cyclobutylpropanoic acid (48a)

Dihydroxypalladium (0.252 g, 1.794 mmol) was charged into a flask andflushed with nitrogen. Ethanol (30 mL) was added followed by a solutionof 2-benzyl-3-cyclobutylisoxazolidin-5-one, 47a, (0.834 g, 3.605 mmol)in approximately 90 mL of ethanol. The reaction mixture was subjected to50 psi of hydrogen for 4 hours. The pressure was vented and the catalystwas filtered off. All volatiles were removed at reduced pressure. ¹H NMRshows the presence of starting material, 47a. The mixture was dissolvedin approximately 100 mL of MeOH and added to 83 mg of 10% Pd/C that hadbeen wet with 20 mL of MeOH. The mixture was subjected to 50 psi of H₂overnight. The pressure was vented and the catalyst was filtered off.All volatiles were removed at reduced pressure to afford 340 mg ofproduct. The resulting crude residue was used without furtherpurification: ¹H NMR (400 MHz, d6-DMSO) δ 3.06-2.83 (m, 1H), 2.28 (ddd,J=23.7, 11.8, 7.7 Hz, 1H), 2.19-1.99 (m, 2H), 1.99-1.56 (m, 6H).

Formation of (+/−)-methyl 3-amino-3-cyclobutylpropanoate (49a)

To a solution of racemic 3-amino-3-cyclobutyl-propanoic acid, 48a, (0.34g, 2.38 mmol) in MeOH (10.2 mL) and benzene (10.2 mL) was addeddiazomethyltrimethyl-silane (3.56 mL of 2 M solution, 7.13 mmol) and thereaction mixture was allowed to stir at room temperature under anitrogen atmosphere overnight. The mixture was diluted with EtOAc andbrine. The layers were separated and the organic phase was dried(MgSO₄), filtered and concentrated in vacuo to afford 354 mg (95%) ofcrude product that was used without further purification: ¹H NMR (400MHz, CDCl₃) δ 3.71-3.66 (m, 3H), 3.18-2.98 (m, 1H), 2.46-2.32 (m, 2H),2.27-1.63 (m, 10H).

Formation of methyl(+/−)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-cyclobutylpropanoate(50a)

To a racemic solution of methyl 3-amino-3-cyclobutylpropanoate, 49a,(0.354 g, 2.252 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.414 g,2.477 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine(0.628 mL, 4.504 mmol). The reaction mixture was heated and stirred at70° C. for 5 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo to approximately 5 mL final volume. The cruderesidue was purified via silica gel chromatography (0-100% EtOAC/hexanesgradient) to afford 289 mg (45%) of the desired product: ¹H NMR (300MHz, CDCl³) δ 7.87 (s, 1H), 5.80 (s, 1H), 4.71-4.38 (m, 1H), 3.68 (s,3H), 2.84-2.37 (m, 3H), 2.23-1.67 (m, 6H); LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, RT=3.08 minutes (M+H) 287.98.

Formation of(+/−)-3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate(51a)

A solution of tripotassium phosphate (0.640 g, 3.021 mmol) in water(1.735 mL) was added to a solution of racemic methyl3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3-cyclobutylpropanoate, 50a,(0.289 g, 1.005 mmol) in 2-methyltetrahydrofuran (5.782 mL). The mixturewas then purged with nitrogen for 20 minutes.5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.460 g, 1.106 mmol) was added and the mixture was purged withnitrogen for an additional 10 minutes.Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (X-Phos:0.029 g, 0.060 mmol) and Pd₂{dba}₃ (0.018 g, 0.020 mmol) were added andthe reaction mixture was warmed to 80° C. and stirred at thistemperature for 5 hours. The mixture was allowed to cool to roomtemperature. The reaction mixture was diluted with water and extractedwith EtOAc. The layers were separated and the organic phase was washedwith brine, dried over MgSO₄, filtered and evaporated to dryness. Thecrude was dissolved in a minimum volume of dichloromethane and purifiedvia silica gel chromatography (0-100% EtOAc/Hexanes). to afford 385 mg(71%) of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, RT=3.68 minutes (M+H) 542.27.

Formation of (+/−)-methyl3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate(52a)

To a racemic solution of methyl3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate,51a, (0.151 g, 0.280 mmol) in methanol (1.5 mL) was added NaOMe (1.5 mLof 25% w/v solution, 6.941 mmol). After stirring the reaction mixture atroom temperature for 5 minutes, the mixture was quenched with aqueoussaturated NH₄Cl solution and diluted with EtOAc and water. The layerswere separated and the organic phase was washed with brine, dried(MgSO₄), filtered and evaporated to dryness. The resulting crude residuewas dissolved in a minimum volume of dichloromethane and purified viasilica gel chromatography (0-100% EtOAc/Hexanes gradient) to afford 108mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, RT=2.29 minutes (M+H) 388.07.

Formation of(+/−)-3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)propanoicacid (44)

To a racemic solution of methyl3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate(0.042 g, 0.109 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added NaOH(0.300 mL of 2 M solution, 0.600 mmol) and the reaction mixture waswarmed to 50° C. After stirring the reaction mixture for 1 hour, themixture was diluted with aqueous saturated NH₄Cl solution and EtOAc. Theorganic layer was dried (MgSO₄), filtered and evaporated to dryness toafford 36 mg of the desired product that was used without furtherpurification: ¹H NMR (400 MHz, d6-DMSO) δ 12.26 (s, 2H), 8.55 (d, J=9.7Hz, 1H), 8.19 (dd, J=45.1, 15.8 Hz, 3H), 7.48 (d, J=8.1 Hz, 1H), 4.79(s, 1H), 2.58 (dd, J=20.6, 12.2 Hz, 2H), 1.85 (ddd, J=29.4, 26.5, 21.1Hz, 7H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,RT=2.10 minutes (M+H) 374.02.

Preparation of Compounds 10, 11, 19, 21, 22, 32, 33, 34, 35, 38, 39, 40,49, 57, and 58

(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutan-1-ol(54a)

A mixture of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (11.09 g, 26.64 mmol),(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol,14a, (6.00 g, 24.22 mmol) and K₃PO₄ (15.42 g, 72.66 mmol) in 2-methylTHF (90 mL) and water (12.00 mL) was purged with nitrogen for 30minutes. X-Phos (0.92 g, 1.94 mmol) and Pd₂(dba)₃ (0.44 g, 0.48 mmol)were added and the reaction mixture was heated at 120° C. in a pressurevial for 2 hr. The reaction mixture was cooled to room temperature,filtered and concentrated in vacuo. The residue was dissolved in EtOAc(100 mL) and washed with water. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified bysilica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 10 gof the desired product as a foamy solid: ¹H NMR (400 MHz, CDCl₃) δ8.54-8.40 (m, 2H), 8.22 (s, 1H), 8.09-8.00 (m, 3H), 7.29-7.16 (m, 2H),5.15 (m, 1H), 4.32-4.14 (m, 1H), 3.98 (m, 1H), 3.70 (m, 1H), 2.30 (s,3H), 1.01 (m, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z502.43 (M+H) RT=1.52 min.

(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutylmethanesulfonate (55a)

Methanesulfonyl chloride (1.83 mL, 23.67 mmol) was added to a cold (0°C.) solution of(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutan-1-ol,54a, (9.50 g, 18.94 mmol) and triethylamine (3.30 mL, 23.67 mmol) indichloromethane (118 mL). The reaction mixture was stirred at roomtemperature for 1 hour. The solvent was removed under reduced pressureand the residue was diluted with water (100 mL) and EtOAc (200 mL). Theorganic layer was separated, dried (MgSO₄), filtered and concentratedunder reduced pressure to afford 10.5 g of the desired product as a paleyellow foam: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 580.41(M+H) RT=2.00 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutylethanethioate (56a)

To a solution of(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutylmethanesulfonate, 55a, (10.5 g, 18.11 mmol) in dry DMF (200 mL) wasadded potassium thioacetate (3.1 g, 27.1 mmol). The brown solution washeated with stirring at 80° C. for 1 hour. The thick brown suspensionwas poured into water and extracted with EtOAc (3×100 mL). The combinedorganic phases were dried (MgSO₄), filtered and concentrated underreduced pressure. The crude residue was purified by silica gelchromatography (0-30% EtOAc/Hexanes gradient) to afford 6.8 g of thedesired product, 56a, as a pale brown solid: ¹H NMR (400 MHz, CDCl₃) δ8.41 (m, 2H), 8.23 (s, 1H), 8.01 (m, 3H), 7.23-7.16 (m, 2H), 4.99 (d,J=10.1 Hz, 1H), 4.37 (m, 1H), 3.21 (dd, J=13.8, 2.3 Hz, 1H), 3.09-2.95(m, 1H), 2.31 (s, 3H), 2.16 (s, 3H), 1.02 (s, 9H); LC/MS (10-90%ACN/water 5 min with 0.9% FA) m/z 560.99 (M+H) RT=4.14 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutane-1-sulfonicacid (57a)

To a cold (0° C.) solution of formic acid (103.4 mL, 2.7 mol) was addedH₂O₂ (34.2 mL of 30% solution, 0.3 mol). The solution was stirred at 0°C. for 1 hour. A solution of(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutylethanethioate, 56a, (6.7 g, 12.0 mmol) in formic acid (20.0 mL) wasadded dropwise. The resulting mixture was stirred at room temperaturefor 2 hours to give a yellow solution. The solvent was removed underreduced pressure to afford the desired product as a foamy pale yellowsolid that was used without further purification: ¹H NMR (400 MHz, MeOD)δ 8.72 (m, 2H), 8.31 (s, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.06 (d, J=8.1 Hz,2H), 7.39 (d, J=8.0 Hz, 2H), 5.08 (d, J=10.0 Hz, 1H), 3.19 (m, 2H), 2.36(s, 3H), 1.04 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18)m/z 566.0 (M+H) RT=2.66 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutane-1-sulfonylchloride (58a)

Oxalyl chloride (3.5 mL, 38.7 mmol) was added to a solution of(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3yl)pyridin-4-ylamino)-3,3-dimethylbutane-1-sulfonicacid, 57a, (7.3 g, 12.9 mmol) in dichloromethane (130 mL), followed bythe slow, dropwise addition of DMF (2 mL). The yellow colored solutionwas stirred at room temperature for 1 hour. The solvent was removedunder reduced pressure to afford 8.4 g of the desired product as a foamyyellow solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 585.72(M+H) RT=2.30 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-N,3,3-trimethylbutane-1-sulfonamide(19)

Methylamine (0.75 mL of 2M solution, 1.53 mmol) was added to a solutionof(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutane-1-sulfonylchloride, 58a, (0.15 g, 0.26 mmol) in THF (1 mL). The solution wasstirred for 1 hour at room temperature and the solvent was then removedunder reduced pressure. The crude sulfonamide was dissolved inacetonitrile (3 mL) and HCl (2 mL of a 4M solution in dioxane) wasadded. The mixture was heated at 65° C. for 3 hours and then cooled toroom temperature. The solvent was removed under reduced pressure and theresulting crude residue was purified by preparative HPLC chromatography(10-80% CH₃CN/water, 0.5% TFA, 15 min) to give 26 mg of the desiredproduct as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 9.75 (s, 1H), 8.12(d, J=9.3 Hz, 1H), 7.94 (s, 1H), 7.73 (s, 2H), 7.67 (brs, 1H), 4.93-4.78(m, 2H), 3.08 (m, 1H), 2.76 (s, 3H), 0.99 (m, 9H); LC/MS (10-90%ACN/water 5 min with 0.9% FA) m/z 425.3 (M+H), RT=2.0 minutes.

The following compounds can be prepared in a similar fashion as theprocedure described above for Compound 19:

(S)—N-Cyclopropyl-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutane-1-sulfonamide(21)

¹H NMR (400 MHz, CDCl₃) δ 8.68 (dd, J=9.6, 2.5 Hz, 1H), 8.24-8.11 (m,2H), 8.03 (d, J=3.8 Hz, 1H), 5.12 (d, J=8.5 Hz, 1H), 3.48 (d, J=9.2 Hz,2H), 2.60-2.47 (m, 1H), 1.13 (s, 9H), 0.68-0.48 (m, 4H): LC/MS (10-90%ACN/water 5 min with 0.9% FA) m/z 451.14 (M+H) RT=2.2 minutes.

(S)-2-(5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-N-(2-methoxyethyl)-3,3-dimethylbutane-1-sulfonamide(35)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 469.28 (M+H) RT=2.11minutes.

(S)-2-(5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethyl-N-propylbutane-1-sulfonamide(34)

¹H NMR (400 MHz, CDCl₃) δ 9.84 (s, 1H), 8.10 (d, J=9.5 Hz, 1H), 7.92 (d,J=1.2 Hz, 1H), 7.72 (d, J=14.2 Hz, 2H), 4.92 (m, 1H), 4.81 (m, 1H), 3.41(d, J=15.0 Hz, 1H), 3.19-2.84 (m, 3H), 1.59-1.38 (m, 3H), 0.98 (s, 9H),0.84 (t, J=7.4 Hz, 3H): LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z453.44 (M+H) RT=2.42 minutes.

(S)-2-(5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-N-isopropyl-3,3-dimethyl-N-propylbutane-1-sulfonamide(39)

¹H NMR (400 MHz, CDCl₃) δ 9.89 (s, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.90 (s,1H), 7.68 (s, 2H), 4.96 (t, J=9.8 Hz, 1H), 4.76 (d, J=9.8 Hz, 1H), 3.60(dd, J=13.0, 6.6 Hz, 1H), 3.42 (m, 1H), 3.09-2.86 (m, 1H), 1.20 (d,J=4.9 Hz, 6H), 0.97 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA)m/z 453.19 (M+H) RT=2.22 minutes.

(S)-2-(5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-N-tert-butyl-3,3-dimethyl-N-propylbutane-1-sulfonamide(40)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 467.20 (M+H) RT=2.36minutes.

(S)—N-Ethyl-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutane-1-sulfonamide(33)

¹H NMR (400 MHz, CDCl₃) δ 9.89 (brs, 1H), 8.07 (d, J=9.3 Hz, 1H), 7.89(s, 1H), 7.66 (m, 2H), 4.95 (t, J=10.2 Hz, 1H), 4.80 (d, J=9.6 Hz, 1H),3.38 (m, 1H), 3.18-2.96 (m, 3H), 1.35-1.12 (m, 3H), 0.90 (m, 9H); LC/MS(10-90% ACN/water 5 min with 0.9% FA) m/z 439.30 (M+H) RT=2.25 minutes.

(S)—N-(2,2-difluoroethyl)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutane-1-sulfonamide(57)

¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J=7.9 Hz, 1H), 7.81 (d, J=2.1 Hz,1H), 7.63 (s, 1H), 7.55 (s, 1H), 5.87 (t, J=54.9 Hz, 1H), 5.03 (t,J=10.4 Hz, 1H), 4.86 (m, 1H), 3.68 (brs, 1H), 3.43 (m, 2H), 3.19 (m,1H), 0.94 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z475.23 (M+H) RT=2.26 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethyl-N-(2,2,2-trifluoroethyl)butane-1-sulfonamide(58)

¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J=9.3, 2.4 Hz, 1H), 7.82 (t, J=11.2Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 5.07 (t, J=10.6 Hz, 1H), 4.77 (m,1H), 3.45 (m, 1H), 3.16-2.99 (m, 1H), 0.97-0.86 (m, 9H); LC/MS (10-90%ACN/water 5 min with 0.9% FA) m/z 493.31 (M+H) RT=2.37 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutane-1-sulfonamide(22)

Concentrated NH₄OH (1.0 mL, 25.7 mmol) was added dropwise to a solutionof(S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-4-ylamino)-3,3-dimethylbutane-1-sulfonylchloride, 58a, (0.3 g, 0.5 mmol) in THF (3 mL). The reaction mixture wasstirred for 15 minutes at room temperature, resulting in a 1-to-1mixture of the desired sulfonamide and sulfonic acid. The solvent wasremoved under reduced pressure. The crude product was purified by silicagel chromatography (0-70% EtOAc/Hexanes gradient) to afford 93 mg of thetosylated sulfonamide intermediate as a foamy solid.

The tosylated sulfonamide (93 mg) was dissolved in THF (10 mL) and asolution of NaOMe (0.15 mL of 25% solution in MeOH, 0.66 mmol) wasadded. The resulting yellow solution was stirred at room temperature for15 minutes and then diluted into aqueous saturated NH₄Cl solution (5mL). The solvent was removed under reduced pressure and the residue wasdissolved in water (10 mL). The aqueous layer was extracted with EtOAc(3×10 mL) and dried (MgSO₄), filtered, and concentrated in vacuo. Thecrude residue was purified by HPLC preparative chromatography (10-80%CH₃CN/water, 0.5% TFA, 15 min) to afford 40 mg of the desired product,22, as a white solid: ¹H NMR (400 MHz, MeOD) δ 8.65 (d, J=9.3, 1H), 8.47(s, 1H), 8.34 (m, 2H), 5.28 (d, J=10.4 Hz, 1H), 3.55 (m, 2H), 1.10 (m,9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 411.0, 1.96 (M+H)RT=1.96 minutes.

(R)-2-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N,3,3-trimethylbutane-1-sulfonamide(38)

¹H NMR (300 MHz, d6-DMSO) δ 12.21 (s, 1H), 8.55 (dd, J=10.0, 2.8 Hz,1H), 8.29-8.23 (m, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.15 (d, J=4.0 Hz, 1H),7.47 (d, J=8.4 Hz, 1H), 6.77-6.69 (m, 1H), 4.88 (t, J=9.1 Hz, 1H),3.49-3.36 (m, 1H), 3.36-3.28 (m, J=10.5 Hz, 1H), 2.55 (t, J=5.6 Hz, 3H),0.98 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, RT=2.11 minutes (M+H) 425.03.

(S)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutane-1-ol(32)

Alcohol, 32, was synthesized in a manner similar to compound 70autilizing the same deprotection procedure, starting with compound 54a:¹H NMR (400 MHz, CDCl₃) δ 10.77 (brs, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.07(s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 5.59 (brs, 1H), 4.36 (t, J=8.3 Hz,2H), 4.11 (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H); LC/MS (10-90% ACN/water 5min with 0.9% FA) m/z 348.13 (M+H) RT=1.83 minutes.

(S)-2-((2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol(49)

Alcohol, 49, was synthesized in a manner similar to compound 32: ¹H NMR(400 MHz, CDCl₃) δ 10.77 (brs, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.07 (s,1H), 8.03 (s, 1H), 7.88 (s, 1H), 5.59 (brs, 1H), 4.36 (t, J=8.3 Hz, 2H),4.11 (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H); LC/MS (10-90% ACN/water 5 minwith 0.9% FA) m/z 348.13 (M+H) RT=1.83 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutane-1-sulfonicacid (11)

Sulfonic acid, 11, was synthesized in a manner similar to Compound 25described below, using compound, 57a, as the starting material: ¹H NMR(400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d,J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H),1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z412.19 (M+H) retention time=1.91 minutes.

(S)-2-((2-(5-chloro-1-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutane-1-sulfonicacid (10)

Sulfonic acid, 10, was synthesized in a manner similar to Compound 11,using5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridineinstead of boronate ester, 7a, as the starting material: ¹H NMR (400MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10(d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19(M+H) retention time=1.91 minutes.

Preparation of Compounds 46

(S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylmethanesulfonate (75a)

To a cold (0° C.) solution of(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-1-ol,14a, (1.95 g, 7.87 mmol) and triethylamine (1.37 mL, 9.84 mmol) indichloromethane (25 mL) was added methanesulfonyl chloride (0.76 mL,9.84 mmol). The solution was stirred at room temperature for 1 hour. Thesolvent was removed under reduced pressure and water (100 mL) and EtOAc(50 mL) were added. The organic phase was separated, dried (MgSO₄) andconcentrated under reduced pressure to afford 2.55 g of the desiredproduct as a pale yellow foamy solid: LC/MS (10-90% ACN/water 5 min with0.9% FA, C4) m/z 326.99 (M+H) RT=2.96 minutes.

(S)—S-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylethanethioate (76a)

Potassium thioacetate (1.30 g, 11.51 mmol) was added to a stirringsolution of(S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylmethanesulfonate, 75a, (2.50 g, 7.67 mmol) in dry DMF (50 mL). Theresulting brown solution was heated with stirring at 78° C. for 1 hour.The brown suspension was poured into water and extracted with EtOAc(3×100 mL). The combined organic phases were dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude residue was purified bysilica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 2.1 gof compound 76a as a pale brown solid: ¹H NMR (400 MHz, CDCl₃) δ 7.81(s, 1H), 5.12 (m, 1H), 4.21 (t, J=9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23(s, 3H), 0.95 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z306.02 (M+H) RT=3.32 min.

(S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutane-1-thiol(77a)

To a nitrogen-purged solution of(S)—S-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylethanethioate, 76a, (1.00 g, 3.27 mmol) in methanol (20 mL) was addedNaOMe (1.457 mL of 25% solution in MeOH, 6.540 mmol) and the solutionwas stirred at room temperature for 1 hour. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in water (25 mL) andslowly acidified with 2N HCl to give a white precipitate that wasextracted twice with EtOAc. The combined organic phases were dried(MgSO₄), filtered and concentrated under reduced pressure to afford 0.85g of the desired product as a pale beige color solid: LC/MS (10-90%ACN/water 5 min with 0.9% FA) m/z 264.92 (M+H) RT=3.32 min.

(S)-2-chloro-N-(3,3-dimethyl-1-(methylthio)butan-2-yl)-5-fluoropyrimidin-4-amine(78a)

To a suspension of(S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutane-1-thiol,77a, (0.85 g, 3.60 mmol) and K₂CO₃ (2.26 g, 16.35 mmol) in acetone wasadded iodomethane (0.82 mL, 13.08 mmol). The suspension was heated at70° C. for 1.30 hours and then cooled to room temperature. The solid wasfiltered and the solution was concentrated under reduced pressure. Thecrude residue was purified by silica gel chromatography (0-10%EtOAc/Hexanes gradient) to afford 310 mg of the desired product as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ 7.81 (s, 1H), 5.12 (m, 1H), 4.21(t, J=9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS(60-90% ACN/water 5 min with 0.9% FA) m/z 278.29 (M+H) RT=1.35 minutes.

(S)-2-chloro-N-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-5-fluoropyrimidin-4-amine(79a)

To a cold (0° C.) solution of(S)-2-chloro-N-(3,3-dimethyl-1-(methylthio)butan-2-yl)-5-fluoropyrimidin-4-amine,78a, (0.15 g, 0.54 mmol) in methanol (10 mL) was added Oxone (0.50 g,0.81 mmol). The solution was stirred at room temperature for 3 hours.The solution was concentrated in vacuo to give a white residue which wasdissolved in water (10 mL). The aqueous layer was extracted with EtOAc(3×10 mL). The combined organic phases were dried (MgSO₄), filtered andconcentrated in vacuo to afford 150 mg of the desired product as a whitesolid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 310.31 (M+H)RT=2.60 minutes.

(S)—N-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine.(80a)

A solution of(S)-2-chloro-N-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-5-fluoropyrimidin-4-amine,79a, (0.15 g, 0.48 mmol),5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.24 g, 0.58 mmol), and K₃PO₄ (0.25 g, 1.16 mmol) in 2-methyl THF (5mL) and water (1 mL) was purged with nitrogen for 30 minutes. X-Phos(0.015 g, 0.031 mmol) and Pd₂(dba)₃ (0.007 g, 0.008 mmol) were added andthe reaction mixture was heated at 120° C. in a pressure vial for 2hours. The reaction mixture was cooled to room temperature, filtered andconcentrated in vacuo. The residue was dissolved in EtOAc (50 mL) andwashed with water. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (0-40% EtOAc/Hexanes gradient) to afford 210 mg of thedesired product as a white foamy solid: ¹H NMR (400 MHz, CDCl₃) δ8.54-8.43 (m, 2H), 8.24 (d, J=1.3 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J=8.2Hz, 2H), 7.23 (s, 1H), 4.99 (dt, J=20.3, 10.1 Hz, 2H), 3.37 (d, J=14.4Hz, 1H), 3.07 (dt, J=31.3, 15.7 Hz, 1H), 2.83 (s, 3H), 2.33 (d, J=19.0Hz, 3H), 0.98 (d, J=20.7 Hz, 9H); LC/MS (10-90% ACN/water 5 min with0.9% FA, C4) m/z 564.20 (M+H) RT=3.70 minutes.

(S)—N-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine(46)

To a solution of(S)—N-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine,80a, (0.21 g, 0.37 mmol) in THF (10 mL) was added NaOMe (0.33 mL of 25%solution in MeOH, 1.45 mmol). The solution was stirred at roomtemperature for 10 minutes, then diluted into aqueous saturated NH₄Clsolution. The solvent was removed under reduced pressure and the residuewas dissolved in water (10 mL). The aqueous layer was extracted withEtOAc (3×10 mL), dried (MgSO₄), filtered and concentrated in vacuo. Theproduct was purified by silica gel chromatography (0-10% MeOH/CH₂Cl₂gradient) to afford 109 mg of the desired product as a white solid: ¹HNMR (400 MHz, CDCl₃) δ 9.38 (s, 1H), 8.53 (d, J=6.9 Hz, 1H), 8.16 (m,2H), 8.06 (s, 1H), 5.09-4.89 (m, 1H), 3.42-3.31 (m, 1H), 3.11 (m, 1H),2.84 (s, 3H), 1.00 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA)m/z 410.19 (M+H) RT=2.03 minutes.

Preparation of Compound 62

Formation of(+/−)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-1-ol(82a)

To a cold (0° C.) solution of racemic methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate(4.00 g, 7.36 mmol) in THF (160 mL) and MeOH (10 mL) was added lithiumborohydride (29.44 mL of 2 M solution, 58.87 mmol) dropwise over 30minutes. The reaction mixture was slowly warmed to room temperature andthen re-cooled to 0° C. A 1N HCl solution (294 mL, 294 mmol) was addeddropwise. The mixture was stirred for 15 minutes and then diluted withdichloromethane. The phases were separated and the aqueous phase wasextracted again with dichloromethane. The combined organic phases werewashed with aqueous saturated NaHCO₃ solution and brine, dried (Na₂SO₄),filtered and concentrated in vacuo. The resulting residue was purifiedvia silica gel chromatography (EtOAc/Hexanes) to afford 3.79 g of thedesired product.

Formation of(+/−)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanal(83a)

To a solution of racemic3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-1-ol,82a, (1.60 g, 3.10 mmol) in THF (64 mL) was added 2-iodoxybenzoic acid(Ibx) (3.86 g, 6.21 mmol). The reaction mixture was heated to refluxunder at atmosphere of nitrogen for 30 minutes. After cooling themixture to room temperature, the solids were filtered. An aqueoussaturated NaHCO₃ solution was added to the filtrate and the biphasicmixture was stirred for 30 minutes. The mixture was further diluted withdichloromethane and the phases separated. The aqueous layer wasextracted again with dichloromethane. The combined organic phases weredried (Na₂SO₄), filtered and concentrated in vacuo. The resultingresidue was purified via silica gel chromatography (EtOAc/Hexanes) toafford 1.59 g of the desired product

Formation of (+/−)-methyl5-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylhept-2-enoate(84a)

To a solution of3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanal,83a, (0.295 g, 0.574 mmol) in toluene (5.9 mL) was added methyl2-(triphenylphosphoranylidene)acetate (0.300 g, 0.862 mmol). The mixturewas stirred overnight at room temperature and then purified directly onsilica gel (EtOAc/Hexanes) to afford 278 mg of the desired product: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.54 minutes(M+H) 584.12.

Formation (+/−)-methyl2,3-dibromo-5-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylheptanoate(85a)

To a solution of racemic methyl5-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylhept-2-enoate,84a, (0.278 g, 0.476 mmol) acetic acid (2.5 mL) was added bromine (0.099g, 0.620 mmol) followed by HBr (0.085 mL of 5.6 M solution in AcOH). Thereaction mixture was heated at 65° C. overnight. The mixture was dilutedinto dichloromethane and aqueous saturated sodium bicarbonate solution.The phases were separated and the aqueous layer was washed withdichloromethane. The organic layers were combined and the solvents wereremoved under reduced pressure. The residue was purified via silica gelchromatography (EtOAc/Hexanes) to give the desired product: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.00 minutes(M+H) 590.94.

Formation of(+/−)-5-(2-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)isoxazol-3-ol(62)

To a solution of NaOH (0.015 g) dissolved in water (0.410 mL) was addedhydroxyurea (0.008 g, 0.100 mmol). The resulting mixture was stirred for30 minutes before the dropwise addition of methyl2,3-dibromo-5-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylheptanoate,85a, (0.064 g, 0.110 mmol) in MeOH (0.150 mL). The solution was stirredfor 6 hours before the addition of AcOH (0.031 mL). The residue waspurified by reverse phase preparative HPLC to afford the desiredproduct: ¹H NMR (300 MHz, MeOD) δ 8.57 (dd, J=9.7, 2.8 Hz, 1H), 8.16 (d,J=5.5 Hz, 2H), 8.00 (d, J=4.1 Hz, 1H), 5.68 (s, 1H), 3.03 (ddd, J=27.4,15.4, 12.3 Hz, 2H), 1.10 (d, J=3.3 Hz, 11H); LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, RT=2.15 minutes (M+H) 416.04.

Preparation of Compound 45

Formation of(+/−)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-1-ol(45)

To a solution of racemic3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-1-ol,82a, (0.187 g, 0.363 mmol) in dioxane (4 mL) was added LiOH (0.91 mL of2 M solution, 1.81 mmol). The reaction mixture was heated at 100° C. for2 hours. The mixture was diluted with water (30 mL) and extracted twicewith EtOAc. The combined organic phases were washed with brine, dried(MgSO4), filtered and concentrated in vacuo. The crude residue waswashed with Hexanes to afford 76 mg of the desired product: ¹H NMR (300MHz, CDCl₃) δ 10.42 (s, 1H), 8.47 (dd, J=9.3, 2.7 Hz, 1H), 8.13 (d,J=11.2 Hz, 1H), 8.10 (s, 1H), 8.04 (d, J=3.2 Hz, 1H), 4.89 (d, J=9.0 Hz,1H), 4.26 (t, J=9.9 Hz, 1H), 3.65 (d, J=9.2 Hz, 1H), 3.54 (td, J=11.4,2.9 Hz, 1H), 2.17-1.99 (m, 1H), 1.40 (dd, J=14.0, 11.9 Hz, 1H), 0.96 (d,J=18.4 Hz, 9H), 0.90-0.73 (m, 1H); LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, (M+H) 362.

Preparation of Compounds 50, 51, and 52

Formation of(+/−)-N-(4,4-dimethyl-1-((2-nitrophenyl)selanyl)pentan-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine(88a)

To a solution of racemic3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentan-1-ol,82a, (1.093 g, 2.120 mmol) and (2-nitrophenyl) selenocyanate (0.722 g,3.180 mmol) in THF (8 mL) was added tributylphosphane (0.792 mL, 3.180mmol). The reaction mixture was stirred overnight and then concentratedunder reduced pressure. The crude residue was purified by silica gel (0to 100% EtOAc/Hexanes gradient) to afford 1.20 g of the desired product.

Formation of(+/−)-N-(4,4-dimethylpent-1-en-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine(89a)

To a cold (0° C.) solution of racemicN-(4,4-dimethyl-1-((2-nitrophenyl)selanyl)pentan-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine,88a, (1.01 g, 1.45 mmol) in chloroform (15 mL) was added mCPBA (0.40 gof 77%, 1.79 mmol). After stirring for 1 hour at room temperature, themixture was diluted with dichloromethane (100 mL) and the resultingsolution was washed with aqueous sodium bicarbonate solution. Theorganic phase was dried (MgSO₄), filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (0 to 100%EtOAc/Hexanes) to afford 623 mg of the desired product: LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 496.76.

Formation of2-(1-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2,2-dimethylpropyl)cyclopropanecarboxylicacid (50, 51, and 52)

To racemicN-(4,4-dimethylpent-1-en-3-yl)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine,89a, (0.105 g, 0.211 mmol) and rhodium(II) acetate (0.019 g, 0.042 mmol)in dichloromethane (6.2 mL) was added dropwise a solution of ethyl2-diazoacetate (0.181 g, 0.166 mL, 1.582 mmol) in 2 mL dichloromethaneover 30 minutes. Pd(OAc)₂ (0.019 g, 0.042 mmol) in dichloromethane (2mL) was added followed by ethyl 2-diazoacetate (0.181 g, 0.166 mL, 1.582mmol) in dichloromethane (2 mL) dropwise. The reaction was stirredovernight and the solvent was concentrated in vacuo. The resulting cruderesidue was purified by silica gel chromatography (0 to 100%EtOAc/Hexanes gradient) to afford a racemic mixture of diasteromericesters, 90a. The mixture of esters was dissolved in dioxane (2 mL) and2N LiOH (1 mL). After heating at 100° C. for 2 h and cooling to roomtemperature, the mixture was acidified pH 6.5 with 2N HCl. The aqueousphase was extracted twice with EtOAc and once with dichloromethane. Thecombined organic phases were dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude residue was subjected to silica gelchromatography (0-20% MeOH/EtOAc gradient) to isolate the mixture ofdiastereomeric acids, which were further purified by preparatory HPLC(CH₃CN/H₂O—TFA modifier) to afford 3 diastereomers. Two of thediastereomers, 51 and 52, were isolated as a single diastereomer each.The third diastereomer, 50, was isolated as a mixture of diastereomers.All three diastereomers showed same LCMS: LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, (M+H) 402.45.

1^(st) fraction—a mixture of diastereomers with 4 peaks at 1.8, 1.9,2.06 and 2.16 minutes—contains 50;

2^(nd) fraction—single peak at 2.06 minutes—(51)

3^(rd) fraction—single peak at 2.16 minutes—(52)

Preparation of Compound 41

Formation of(+/−)-2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile(95a)

To a solution of 3-amino-4,4-dimethylpentan-1-ol (2.00 g, 8.64 mmol) inethanol (20 mL) was added racemic2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (1.65 g, 8.64 mmol) and 5mL of N,N,-diisopropylethylamine. The solution was stirred at 75° C. for12 hours and concentrated in vacuo. The residue was purified by silicagel chromatography (methylene chloride), yielding 2.2 g of2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile,95a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.02minutes (M+H) 286.16

Formation of(+/−)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile(41)

To a racemic solution of2-chloro-5-fluoro-6-(1-hydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile,95a, (0.20 g, 0.70 mmol) and5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,7a, (0.44 g, 1.05 mmol) in THF (15 mL) was added a solution of potassiumphosphate (0.45 g) in 3 mL of water. The resulting mixture was degassedunder a stream of nitrogen for 15 minutes. To the mixture was then addedX-Phos (0.03 g, 0.07 mmol) and Pd₂(dba)₃ (0.02 g, 0.04 mmol). Thereaction was warmed to 135° C. via microwave irradiation for 15 minutesand then extracted into EtOAc (3×15 mL) vs. water. The organic layerswere combined and concentrated in vacuo to a dark oil which wasredissolved in 20 mL of THF. To the solution was added 5 mL of 2 N LiOHand the reaction was warmed to 65° C. for 12 hrs and then concentratedin vacuo. The resulting residue was purified via silica gelchromatography (EtOAc) to afford 108 mg of the desired product, 41, as ayellow solid: ¹H NMR (300 MHz, d6-DMSO) δ 12.40 (s, H), 8.63 (dd, J=2.8,10.1 Hz, H), 8.37-8.32 (m, H), 7.83 (d, J=11.4 Hz, H), 7.31 (d, J=9.7Hz, H), 4.56-4.50 (m, H), 4.41 (dd, J=4.1, 5.2 Hz, H), 3.69 (s, H), 3.57(s, H), 3.49 (t, J=6.6 Hz, H), 3.48 (s, H), 3.36-3.28 (m, H), 2.50 (qn,J=1.8 Hz, H), 1.86-1.67 (m, 2H), 1.21 (dd, J=7.0, 16.1 Hz, H) and 0.94(s, 9H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,RT=3.09 minutes (M+H) 386.39.

Preparation of Compounds 11, 24, 25 26, 27, 28, 29, 30, and 31

(S)-2-chloro-5-fluoro-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile(97a)

A mixture of 2-chloro-5,6-difluoropyridine-3-carbonitrile (6.52 g, 34.13mmol), (2S)-2-amino-3,3-dimethyl-butan-1-ol (4.00 g, 34.13 mmol) andtriethylamine (9.51 mL, 68.26 mmol) in CH₃CN (50 mL) and THF (50 mL) washeated at 80° C. for 4 hours. The mixture was cooled to room temperatureand the solvent was evaporated under reduced pressure. The crude productwas purified via silica gel chromatography (0-60% EtOAc/Hexanesgradient) to afford 6.7 g of the desired product as an off white solid:¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J=9.7 Hz, 1H), 5.32 (m, 1H),4.19-4.08 (m, 1H), 3.95-3.83 (m, 1H), 3.74-3.51 (m, 1H), 0.92 (s, 9H);LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 272.02 (M+H), retentiontime 1.02 minutes.

(S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile(98a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (1.84 g, 4.42 mmol),(S)-2-chloro-5-fluoro-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile,97a, (1.00 g, 3.68 mmol) and K₃PO₄ (2.40 g, 11.22 mmol) in 2-methyl-THF(12 mL) and water (2 mL) was purged with nitrogen for 30 minutes. X-Phos(0.14 g, 0.294 mmol) and Pd₂(dba)₃(0.07 g, 0.07 mmol) were added and thereaction mixture was heated at 120° C. in a pressure vial for 2 hours.The reaction mixture was cooled to room temperature, filtered andconcentrated in vacuo. The residue was dissolved in EtOAc (50 mL) andwashed with water. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo. The crude product was purified by silica gelchromatography (0-40% EtOAc/Hexanes gradient) to afford 1.88 g as afoamy solid: ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 8.36 (d, J=2.0 Hz,1H), 8.26 (m, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.46 (d, J=12 Hz, 2H), 7.33(d, J=7.5 Hz, 1H), 5.34 (m, 1H), 4.42-4.31 (m, 1H), 4.02 (m, 1H), 3.75(m, 1H), 2.40 (s, 3H), 1.26 (s, 9H); LC/MS (60-90% ACN/water 5 min with0.9% FA, C4) m/z 526.49 (M+H), retention time=1.83 minutes.

(S)-2-((5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-3,3-dimethylbutylmethanesulfonate (99a)

To a cold (0° C.) solution of(S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile,98a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) indichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL,8.96 mmol). The solution was stirred at room temperature for 1 hour. Thesolvent was removed under reduced pressure and water (100 mL) and EtOAc(200 mL) were added. The organic phase was separated, dried (MgSO₄),filtered and concentrated under reduced pressure to afford 4.22 g of thedesired product as a yellow foamy solid that was used without furtherpurification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45(M+H) retention time=2.03 minutes.

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-ylamino)-3,3-dimethylbutylethanethiolate (100a)

Potassium thioacetate (1.2 g, 10.5 mmol) was added to a solution of(S)-2-((5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-3,3-dimethylbutylmethanesulfonate, 99a, (4.22 g, 6.99 mmol) in dry DMF (90 mL). The brownsolution was heated with stirring at 80° C. for 1 hour. The thick brownsuspension was poured into water and extracted with EtOAc (3×100 mL).The organic layers were dried (MgSO₄), filtered and concentrated underreduced pressure. The crude product was purified by silica gelchromatography (0-30% EtOAc/Hexanes gradient) to afford 6.8 g of thedesired product as a pale brown solid: ¹H NMR (400 MHz, CDCl₃) δ 8.57(s, 1H), 8.28 (d, J=1.3 Hz, 1H), 8.11 (dd, J=8.5, 2.3 Hz, 1H), 8.05 (d,J=8.3 Hz, 2H), 7.33 (d, J=10.2 Hz, 1H), 7.24 (d, J=8.3 Hz, 2H), 5.11 (m,1H), 4.31 (m, 1H), 3.19 (dd, J=14.0, 3.0 Hz, 1H), 3.03 (dt, J=13.6, 6.9Hz, 1H), 2.31 (s, 3H), 2.10 (m, 3H), 10.97 (s, 9H); LC/MS (60-90%ACN/water 5 min with 0.9% FA) m/z 584.0 (M+H) retention time=2.66minutes.

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2-ylamino)-3,3-dimethylbutane-1-sulfonicacid (101a)

To a cold (0° C.) solution of formic acid (22.2 mL, 588.5 mmol) wasadded H₂O₂(7.35 mL of 30% solution, 71.96 mmol). The mixture was stirredat 0° C. for 1 hour. A solution of(S)—S-2-(5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2ylamino)-3,3-dimethylbutylethanethiolate, 99a, (1.5 g, 2.57 mmol) in formic acid (5 mL) was addeddropwise to the reaction mixture. The resulting solution was stirred for2 hours at room temperature. The solvent was removed under reducedpressure 1.72 g of the desired sulfonic acid as a pale yellow foamysolid: LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 586 (M+H)retention time=3.95 minutes.

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2ylamino)-3,3-dimethylbutane-1-sulfonylchloride (102a)

To a solution of(S)-2-(5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2ylamino)-3,3-dimethylbutane-1-sulfonicacid, 101a, (1.5 g, 2.54 mmol) and DMF (0.5 mL) in dichloromethane (30mL) was added oxalyl dichloride (0.68 mL, 7.63 mmol) dropwise. Thesolution was stirred at room temperature for 1 hour. The solvent wasremoved under reduced pressure to afford 1.6 g of the desired product asa yellow solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 608(M+H) retention time=2.40 minutes.

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2ylamino)-N,3,3-trimethylbutane-1-sulfonamide(26)

Methyl amine (0.41 mL of 2M solution, 0.82 mmol) was added to a solutionof(S)-2-(5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-2ylamino)-3,3-dimethylbutane-1-sulfonylchloride, 102a, (0.10 g, 0.16 mmol) in THF (1 mL). The solution wasstirred for 1 hour at room temperature and the solvent was removed underreduced pressure. The crude sulfonamide was dissolved in CH₃CN (3 mL)and HCl (2 mL of 4M solution in dioxane) was added. The reaction mixturewas heated at 65° C. for 3 hours and then cooled to room temperature.The solvent was removed under reduced pressure and the resulting residuewas purified by preparative HPLC chromatography (10-80% CH₃CN/water,0.5% TFA, 15 min) to afford 26 mg of the desired product as a whitesolid: ¹H NMR (400 MHz, CDCl₃) δ 9.68 (s, 1H), 8.45-8.33 (m, 1H), 8.17(d, J=2.8 Hz, 1H), 7.88 (s, 1H), 7.36 (d, J=10.3 Hz, 1H), 6.47 (d, J=4.9Hz, 1H), 5.11 (d, J=7.8 Hz, 1H), 4.90 (d, J=10.4 Hz, 1H), 3.52 (s, 1H),3.04 (dd, J=15.0, 10.5 Hz, 1H), 2.67 (d, J=5.0 Hz, 3H), 1.02 (s, 9H);LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 449.22 (M+H) retentiontime=2.97 minutes.

The following compounds can be prepared in a similar fashion as theprocedure described above for Compound 26:

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2ylamino)-N,N,3,3-tetramethylbutane-1-sulfonamide(27)

¹H NMR (400 MHz, CDCl₃) δ 8.59 (dd, J=9.7, 2.6 Hz, 1H), 8.38 (s, 1H),8.21 (s, 1H), 7.31 (m, 1H), 5.12 (brs, 1H), 4.97 (brs, 1H), 3.33 (m,1H), 2.70 (s, 6H), 0.95 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9%FA) m/z 463.49 (M+H) retention time=3.12 minutes.

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2ylamino)-N-cyclopropyl-3,3-dimethylbutane-1-sulfonamide(28)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 475.0 (M+H) retentiontime=3.12 minutes.

(S)-2-((5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-N-(2-methoxyethyl)-3,3-dimethylbutane-1-sulfonamide(29)

¹H NMR (400 MHz, MeOD) δ 8.71 (dd, J=9.7, 2.6 Hz, 1H), 8.37 (s, 1H),8.20 (s, 1H), 7.57 (d, J=10.9 Hz, 1H), 5.08 (d, J=8.8 Hz, 1H), 3.54-3.40(m, 2H), 3.32 (m, 5H), 3.15 (t, J=5.4 Hz, 2H), 1.03 (s, 9H); LC/MS(10-90% ACN/water 5 min with 0.9% FA) m/z 493.50 (M+H) retentiontime=3.05 minutes.

(S)-2-((5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-3,3-dimethyl-N-propylbutane-1-sulfonamide(31)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 477.65 (M+H) retentiontime=3.27 minutes.

(S)-2-((5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-3,3-dimethylbutane-1-sulfonamide(30)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 435.46 (M+H) retentiontime=2.80 minutes.

(S)-5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile(24)

Alcohol, 24, was synthesized in a manner similar to compound 32utilizing the same deprotection procedure, starting with compound 98a:¹H NMR (400 MHz, CDCl₃) δ 10.27 (brs, 1H), 8.25 (d, J=9.4 Hz, 1H), 8.17(s, 1H), 8.11 (s, 1H), 7.23 (d, J=10.3 Hz, 1H), 5.20 (d, J=9.6 Hz, 1H),4.41 (t, J=7.4 Hz, 1H), 4.09 (d, J=11.3 Hz, 1H), 3.82-3.58 (m, 1H), 0.99(d, J=19.5 Hz, 9H).

(S)-2-(5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3,3-dimethylbutane-1-sulfonicacid (25)

To a solution of(S)-2-((5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-3,3-dimethylbutane-1-sulfonicacid, 101a, (0.12 g, 0.21 mmol) in CH₃CN (5 mL) was added HCl (2 mL of4M solution in dioxane). The reaction mixture was heated at 100° C. for18 hours in a pressure vial and then cooled to room temperature. Thesolvent was removed under reduced pressure and the product was purifiedby preparative HPLC chromatography (10-80% CH₃CN/water, 0.5% TFA, 15min) to give 42 mg of the desired product as an off-white solid: ¹H NMR(400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d,J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (m, 1H), 3.46-3.33 (m, 3H), 1.10 (s,9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 449.22 (M+H).

(S)-2-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutane-1-sulfonicacid (11)

Sulfonic acid, 11, was synthesized in a manner similar to compound 30,using compound 57a: ¹H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd,J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 minwith 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.

Preparation of Compounds 62, 87, and 88

Formation of ethyl 1-methylcyclobutanecarboxylate (111a)

A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF(160 mL) was added dropwise to a cold (−78° C.) solution of LDA (164mmol of 2M solution) in THF (40 mL). The solution was warmed to 0° C.and then cooled again to −40° C. before the addition of iodomethane(10.2 mL, 163.8 mmol). The solution was slowly warmed to roomtemperature and stirred overnight. The reaction was quenched with anaqueous saturated solution of ammonium chloride and ether was added. Thelayers were separated and the aqueous layer was washed with ether. Thecombined organic layers were washed with 1N HCl then dried over MgSO₄.The product was purified by distillation: ¹H NMR (400 MHz, MeOD) δ4.20-4.05 (m, 2H), 2.57-2.33 (m, 2H), 2.08-1.94 (m, 1H), 1.94-1.77 (m,3H), 1.40 (s, 3H), 1.27 (tt, J=7.1, 1.5 Hz, 3H).

Formation of (1-methylcyclobutyl)methanol (112a)

Lithium aluminum hydride (2.1 g, 59.4 mmol) was suspended in ether (150mL) and cooled to 0° C. A solution of ethyl1-methylcyclobutanecarboxylate, 111a, (13.0 g, 91.4 mmol) in ether (60mL) was added dropwise to the LiAlH₄ suspension. The mixture was stirred2 hours in an ice bath then quenched slowly with 1N HCl. The layers wereseparated and the aqueous layer was washed with ether. The combinedorganic layers were washed with brine and the volatiles were removedwith a gentle stream of nitrogen to afford the desired product that wasused without further purification: ¹H NMR (400 MHz, CDCl₃) δ 3.54-3.39(m, 4H), 1.99-1.74 (m, 8H), 1.74-1.62 (m, 4H), 1.46-1.18 (m, 3H), 1.13(d, J=1.7 Hz, 6H).

Formation of 1-methylcyclobutanecarbaldehyde (113a) and methyl3-(1-methylcyclobutyl)acrylate (114a)

A solution of (1-methylcyclobutyl)methanol, 112a, (1.00 g, 9.98 mmol) indichloromethane (25 mL) was added to a suspension of PCC (2.69 g, 12.50mmol) and Celite (2.70 g) in dichloromethane (25 mL). The reactionmixture was stirred 2 hours and filtered through a pad of silica gel(eluting with dichloromethane). The solvents were removed with a streamof nitrogen until volume was approximately 20 mL.2-(triphenyl-phosphoranylidene)acetate (0.98 g, 10.00 mmol) was added inone portion and the mixture was stirred for 7 hours. The volatiles wereremoved under reduced pressure and a solution of 10% Hexanes/ether wasadded. The resulting solid was filtered off and discarded. The resultingsolution was poured directly on silica gel and eluted with EtOAc/Hexanesto afford the desired product: ¹H NMR (400 MHz, CDCl₃) δ 7.05 (d, J=15.8Hz, 1H), 5.66 (dd, J=15.8, 1.3 Hz, 1H), 4.21-4.00 (m, 2H), 2.12-1.73 (m,7H), 1.29-1.17 (m, 6H).

Formation (+/−)-2-benzyl-3-(1-methylcyclobutyl)isoxazolidin-5-one (115a)

N-benzylhydroxylamine (hydrochloric acid) (0.28 g, 1.80 mmol) andtriethylamine (0.28 mL, 2.00 mmol) were added to a solution of methyl3-(1-methylcyclobutyl)acrylate, 114a, (0.26 g, 1.50 mmol) indichloromethane (9.5 mL). The reaction mixture was stirred at 50° C.overnight. The reaction mixture was cooled to room temperature and themixture was diluted with dichloromethane and water. The layers wereseparated with a phase separator and the aqueous layer was washed withdichloromethane. The organic layers were combined and the volatilesremoved under reduced pressure. The residue was purified on silica gel(EtOAc/Hexanes) to afford the desired product as a racemic mixture: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.47 minutes(M+H) 246.10.

Formation of (+/−)-3-amino-3-(1-methylcyclobutyl)propanoic acid (116a)

A solution of racemic 2-benzyl-3-(1-methylcyclobutyl)isoxazolidin-5-one,115a, (0.18 g, 1.28 mmol) in MeOH (2.9 mL) was shaken overnight under 50psi hydrogen in the presence of 50 mg palladium hydroxide catalyst. Themixture was filtered through Celite and the volatiles were removed underreduced pressure to afford the desired product that was used withoutfurther purification: ¹H NMR (400 MHz, MeOD) δ 3.42 (dd, J=11.0, 1.9 Hz,1H), 2.26 (ddd, J=27.8, 16.7, 6.5 Hz, 2H), 1.86 (dddd, J=36.9, 26.3,11.2, 7.6 Hz, 6H), 1.18 (s, 3H).

Formation of (+/−)-methyl3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate(118a)

Racemic 3-amino-3-(1-methylcyclobutyl)propanoic acid, 116a, (2.3 g, 14.4mmol) was dissolved in methanol (104 mL). The solution was cooled in anice bath and acetyl chloride (5.6 g, 71.9 mmol) was added dropwise (Tempkept <10° C.). The reaction mixture was heated to 65° C. and stirred atthat temperature for 3 hours. The reaction mixture was cooled to roomtemperature and then flushed with toluene to remove volatiles. Cruderacemic 3-methoxy-1-(1-methylcyclobutyl)-3-oxopropan-1-aminium chloride,117a, was used without further purification.

Racemic 3-methoxy-1-(1-methylcyclobutyl)-3-oxopropan-1-aminium chloride,117a, (3.3 g, 15.9 mmol) was dissolved in a mixture of 59 mL THF and 6.6mL EtOH and the solution was cooled in an ice bath.2,4-Dichloro-5-fluoro-pyrimidine (2.9 g, 18.0 mmol) was added followedby dropwise addition of triethylamine (5.1 g, 51.0 mmol). The reactionmixture was stirred at 55° C. for 17 hours. The reaction mixture wascooled to room temperature after which water and dichloromethane wereadded. The phases were separated and the aqueous layer was washed withdichloromethane. The organic layers were combined and washed with brine.The solvents were removed and the residue was purified via silica gelchromatography (EtOAc/Hexanes) to afford the desired product: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.23 minutes(M+H) 302.35.

Formation of (+/−)-methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate(119a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (3.31 g, 7.95 mmol), racemic methyl3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate,118a, (2.00 g, 6.63 mmol) and K₃PO₄ (4.22 g, 20.00 mmol) in 2-MeTHF (253mL) and water (56 mL) was purged with nitrogen for 0.75 h. XPhos (0.38g, 0.80 mmol) and Pd₂(dba)₃ (0.15 g, 0.17 mmol) were added and thereaction mixture was stirred at 115° C. in a sealed tube for 2 hours.The reaction mixture was cooled and the aqueous phase was removed. Theorganic phase was filtered through a pad of Celite and the mixture wasconcentrated to dryness. The residue was purified via silica gelchromatography (EtOAc/Hexanes) to afford the desired product: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.32 minutes(M+H) 556.44.

Formation of (+/−)-methyl3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate(120a)

To a racemic solution of methyl3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate,119a, (3.3 g, 5.9 mmol) in acetonitrile (25 mL) was added HCl (26 mL of4N solution in dioxane). The reaction mixture was heated to 65° C. for 4hours. The solution was cooled to room temperature and the solvents wereremoved under reduced pressure. The mixture was flushed withacetonitrile after which aqueous sodium bicarbonate and ethyl acetatewere added. The phases were separated and the aqueous layer washed withethyl acetate. The combined organic phases were dried with Na₂SO₄,filtered and concentrated in vacuo. The resulting residue was purifiedvia silica gel chromatography (EtOAc/Hexanes) to afford the desiredproduct: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,RT=2.34 minutes (M+H) 403.11.

Formation of3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoicacid (87 and 88)

To a solution of methyl3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclobutyl)propanoate(11) (1.75 g, 4.36 mmol) in THF (25 mL) was added aqueous 1N LiOH (13.1mL). The mixture was heated to 50° C. for 3.5 hours. The reactionmixture was cooled to room temperature and diluted with water. The THFwas removed under reduced pressure and the residue was then flushedtwice with hexanes. Ether was added and the layers separated (the etherlayer was discarded). The pH was adjusted to 5.5 with 1N HCl and theresulting solid was filtered and washed with water. The solid wasflushed with heptanes and dried over P₂O₅ to give the desired product:¹H NMR (400 MHz, DMSO) δ 12.17 (d, J=60.2 Hz, 2H), 8.59 (d, J=8.4 Hz,1H), 8.39-8.05 (m, 3H), 7.52 (s, 1H), 5.00 (s, 1H), 2.23 (d, J=7.7 Hz,1H), 2.00 (s, 1H), 1.81 (d, J=48.3 Hz, 2H), 1.62 (s, 1H), 1.46 (s, 1H),1.21 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, RT=2.08 minutes (M+H) 388.46. The racemic mixture was submittedto SFC chiral separation to obtain the individual enantiomers, 87 and88.

Preparation of Compound 65

Formation of(+/−)-3-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanenitrile(124a)

Ammonium chloride (0.12 g, 2.30 mmol) was suspended in toluene (4.5 mL).The mixture was cooled in an ice bath and AlMe₃ (1.15 mL of a 2 Msolution in toluene, 2.30 mmol) was added dropwise. The mixture wasstirred 30 minutes and another 30 min at room temperature. A solution ofracemic methyl3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentanoate(0.25 g, 0.46 mmol) in 4.5 mL toluene was added and the resultingmixture was stirred 60° C. overnight. The reaction mixture was cooled inan ice bath and quenched with 1N HCl. The mixture was extracted withdichloromethane and filtered through a phase separator. The residue waspurified on silica gel (EA/Hex): LCMS Gradient 10-90%, 0.1% formic acid,5 minutes, C18/ACN, RT=2.04 minutes (M+H) 511.42.

Formation of(+/−)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-N′-hydroxy-4,4-dimethylpentanimidamide(125a)

To a solution of racemic3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentanenitrile,124a, (0.059 g, 0.116 mmol) in DMSO (0.500 mL) was added hydroxylamine(0.031 g, 0.470 mmol). The mixture was heated in a microwave at 140° C.for 30 minutes. The residue was purified on a C18 column(acetonitrile/0.1% formic acid) to afford the desired product: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.58 minutes(M+H) 390.06.

Formation of(+/−)-3-(2-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1,2,4-oxadiazol-5(2H)-one(65)

To a solution of racemic3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-N′-hydroxy-4,4-dimethyl-pentanamidine,125a, (0.034 g, 0.087 mmol) and carbonyl diimidazole (0.014 g, 0.087mmol) in THF (1 mL) was added N,N-diisopropylethylamine (0.045 mL, 0.260mmol). The reaction mixture was stirred at room temperature for 48hours. Aqueous ammonium chloride and dichloromethane were added and thelayers were separated with a phase separator. The residue was purifiedon a C18 column (acetonitrile/0.1% formic acid) to afford the finalproduct: ¹H NMR (400 MHz, Acetone) δ 11.23 (s, 1H), 8.54 (dd, J=9.8, 2.8Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.13 (d, J=3.7 Hz, 1H), 6.81 (s,1H), 5.00 (d, J=11.2 Hz, 1H), 3.15 (d, J=14.8 Hz, 3H), 2.94 (dd, J=14.4,11.9 Hz, 2H), 1.16 (s, 8H); LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, RT=1.58 minutes (M+H) 390.06.

Preparation of Compound 47

(R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (128a)

Sulfoxide, 127a, was prepared in same fashion as sulfoxide, 25a, (seeSynthetic Scheme 4) using 2,4-dichloropyrimidine instead of2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine.

A mixture of5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine,127a, (0.052 g, 0.121 mmol) and (3R)-3-amino-4,4-dimethyl-pentanoicacid, 2a, (0.035 g, 0.242 mmol) along with Na₂CO₃ (0.051 g, 0.483 mmol)in a mixture of THF (0.780 mL) and acetonitrile (0.260 mL) was heated to125° C. for 30 minutes under microwave irradiation. Then, thetemperature was raised to 150° C. for a further 2.5 hours. The mixturewas neutralized with aqueous 2N HCl and extracted with several portionsof EtOAc. The organic solvents were evaporated in vacuo. Purification byflash chromatography (SiO₂, 0-100% hexanes-EtOAc (with 10% MeOH))provided 19 mg of the desired material (31% yield), which was used inthe next step without further purification: LCMS Gradient 10-90%, 0.1%trifluoroacetic acid, 5 minutes, C18/ACN, RT=2.70 minutes (M+H) 512.00.

(R)-3-((2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (47)

To a solution of(R)-3-((2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid, 128a (0.019 g, 0.037 mmol) in acetonitrile (0.6 mL) was added HCl(0.15 mL of 4 M in dioxane, 0.60 mmol). The solution was heated to 60°C. for 18 hours. Then, additional HCl (0.36 mL of 4 M in dioxane) wasadded and heating was continued for 4 hours. The mixture was cooled andconcentrated in vacuo. Trituration with Et₂O followed by purification bypreparatory HPLC provided 17.5 mg of the desired product as a TFA salt.The NMR indicated a 4 to 1 ratio of atropisomers: ¹H NMR (400 MHz, MeOD,major atropsomer) δ 8.70 (dd, J=8.9, 2.3 Hz, 1H), 8.50 (s, 1H), 8.35 (s,1H), 7.99 (d, J=7.3 Hz, 1H), 6.60 (d, J=7.2 Hz, 1H), 5.05 (d, J=10.7 Hz,1H), 2.93 (dd, J=15.9, 1.8 Hz, 1H), 2.53 (dd, J=15.9, 11.2 Hz, 1H), 1.08(d, J=0.8 Hz, 9H); LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5minutes, C18/ACN, RT=2.17 minutes (M+H) 358.02.

Preparation of Compound 48

Formation of 2-chloro-5-fluoropyridine-3-carboxamide (130a)

To the suspension of 2-chloro-5-fluoropyridine-3-carboxylic acid (37.0g, 210.8 mmol) in dichloromethane (555 mL) was added oxalyl chloride(56.2 g, 442.7 mmol) under nitrogen. DMF (1.54 g, 21.08 mmol) was addedslowly to the reaction mixture. The mixture was stirred at roomtemperature for 2 h and dichloromethane was removed under reducedpressure. The residue was dissolved in THF (300 mL) and cooled down to0° C. by ice bath. Ammonium hydroxide (28-30%, 113.0 mL, 1.8 mmol) wasadded in one portion. The mixture was stirred for another 15 min. Themixture was diluted into ethyl acetate (300 mL) and water (300 mL) andthe phases were separated. The organic layer was washed with brine anddried over Na₂SO₄, filtered, and concentrated in vacuo to afford 29.8 gdesired product as white solid: ¹H NMR (300 MHz, DMSO-d6) δ 8.53 (d,J=3.0 Hz, 1H), 8.11 (s, 1H), 8.00 (dd, J=8.0, 3.0 Hz, 1H), 7.89 (s, 1H);LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=1.11minutes, (M+H) 175.02.

Formation of 2-chloro-5-fluoropyridine-3-carbonitrile (131a)

To a suspension of 2-chloro-5-fluoropyridine-3-carboxamide, 130a, (29.8g, 170.4 mmol) in dichloromethane (327 mL) was added triethylamine (52.3mL, 374.9 mmol). This mixture was cooled down to 0° C. Trifluoroaceticanhydride (26.1 mL, 187.4 mmol) was added slowly over period of 15 min.The mixture was stirred at 0° C. for 90 min. The mixture was dilutedinto dichloromethane (300 mL) and the resulting organic phase was washedwith aqueous saturated NaHCO₃ solution (300 mL) and brine (300 mL). Theorganic layer was dried over Na₂SO₄, filtered, concentrated in vacuo.The product was purified by silica gel chromatography (40% to 60% ethylacetate/hexanes gradient) giving 24.7 g of product as a white solid: ¹HNMR (300 MHz, CDCl₃) δ 8.50 (d, J=3.0 Hz, 1H), 7.77 (dd, J=6.8, 3.0 Hz,1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=2.50 minutes, (M+H) 157.06.

Formation of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine (132a)

To the mixture of 2-chloro-5-fluoropyridine-3-carbonitrile, 131a, (29.6g, 157.1 mmol) in n-butanol (492 mL) was added hydrazine hydrate (76.4mL, 1.6 mol). This mixture was heated to reflux for 4.5 h and cooleddown. n-Butanol was removed under reduced pressure and water (300 mL)was added resulting in a yellow precipitate. The suspension was filteredand washed with water twice, followed by a MTBE wash. The yellow solidwas dried in a vacuum oven to give 18 g of the desired product: ¹H NMR(300 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.38 (dd, J=2.7, 1.9 Hz, 1H), 7.97(dd, J=8.8, 2.7 Hz, 1H), 5.56 (s, 2H). LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=1.25 minutes (M+H) 152.95.

Formation of 3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine (133a)

To a mixture of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine, 132a, (0.88g, 5.79 mmol) in bromoform (8.8 mL) was added tert-butyl nitrite (1.38mL, 11.57 mmol). This mixture was heated to 61° C. for 1 h and thenheated to 90° C. for an additional hour. The mixture was cooled to roomtemperature and bromoform was removed under reduced pressure. Theresulting crude residue was purified by silica gel chromatography (5-50%ethyl acetate/hexanes) to afford 970 mg of the desired product as awhite solid: ¹H NMR (300 MHz, DMSO-d6) δ 14.22 (s, 1H), 8.67 (dd, J=2.7,1.9 Hz, 1H), 8.07 (dd, J=8.2, 2.7 Hz, 1H); LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, Retention Time=2.42 minutes (M+H)216.11.

Formation of 3-bromo-5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridine (134a)

A mixture of 3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine, 133a, (0.97 g,4.49 mmol) and K₂CO₃ (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to0° C. Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. Themixture was stirred at room temperature overnight. The mixture wasdiluted into ethyl acetate (40 mL) and water (30 mL) and the layers wereseparated. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The product was purified by silicagel chromatography (40% ethyl acetate/hexanes) to afford 1.68 g of thedesired product as a white solid: ¹H NMR (300 MHz, DMSO-d6) δ 8.45-8.38(m, 1H), 8.04 (dd, J=8.0, 2.7 Hz, 1H), 7.35-7.16 (m, 15H); LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.03minutes (M+H) 459.46.

Formation of5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine(135a)

A solution of 3-bromo-5-fluoro-1-trityl-pyrazolo[3,4-b]pyridine, 134a(3.43 g, 7.48 mmol), KOAc (2.20 g, 22.45 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(2.85 g, 11.23 mmol) in DMF (50 ml) was degassed under a stream ofnitrogen for 40 min. To the mixture was added Pd(dppf)₂Cl₂ (0.610 g,0.748 mmol) The reaction mixture was heated at 100° C. for 90 minutes.The reaction mixture was filtered through a pad of Celite. To theresulting filtrate was added ether and brine. The organic phase wasdried over MgSO₄, filtered and concentrated in vacuo to afford 4.0 gcrude product that was used in the next step without furtherpurification (note, the product decomposes if purification is attemptedvia silica gel chromatography).

Formation of5-fluoro-3-(4-(methylthio)pyrimidin-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine(136a)

A solution of 2-chloro-4-methylsulfanyl-pyrimidine (0.25 g, 1.56 mmol),K₃PO₄ (0.99 g, 4.67 mmol) and5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine,135a, (0.87 g, 1.71 mmol) in water (1 mL) and 2-methyltetrahydrofuran (9mL) was degassed under a stream of nitrogen for 15 minutes. Then,Pd₂(dba)₃ (0.04 g, 0.05 mmol) was added and the mixture was degassed foran additional 2-3 minutes. The vessel was sealed and heated to 95° C.overnight. After separating the layers, the organic phase was washedwith water. The resulting solid was filtered and washed with ether andMeTHF. Filtered through PSA cartridge with MeOH/dichloromethane mixtureto give the desired product as a white solid: LCMS Gradient 60-98%, 0.1%formic acid, 7 min, C4/ACN, Retention Time=2.68 min (M+Na) 526.1.

Formation of5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine(137a)

To a cold (0° C.) mixture of5-fluoro-3-(4-(methylthio)pyrimidin-2-yl)-1-trityl-1H-pyrazolo[3,4-b]pyridine,135a, (0.70 g, 1.38 mmol) in dichloromethane (10.4 mL) was added mCPBA(0.43 g, 1.93 mmol). After 30 minutes, the mixture was diluted withdichloromethane and washed with 2N NaOH and brine. The organic phase wasbrine dried over Na₂SO₄, filtered and stripped down twice with CH₃CN toafford 660 mg of desired product that was used without furtherpurification: LCMS Gradient 60-98%, 0.1% formic acid, 7 min, C4/ACN,Retention Time=2.68 minutes (M+H) 520.

(R)-3-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (138a)

A stirred suspension of5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-1-trityl-1H-indazole,137a, (0.09 g, 0.18 mmol), (3R)-3-amino-4,4-dimethyl-pentanoic acid(0.05 g, 0.36 mmol) and Na₂CO₃ (0.76 g, 0.72 mmol) in acetonitrile (0.62mL) and 2-MeTHF (0.31 mL) was heated to 125° C. in microwave reactor for1 hour. After cooling to room temperature, the mixture was diluted withEtOAc, neutralized with HCl (0.72 mL of 2 M solution, 1.42 mmol) and theproduct was extracted with several portions of EtOAc and CH₂Cl₂.Evaporation of the combined organic phases provided 109 mg of thedesired crude product which was used in the next reaction withoutfurther purification: LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5minutes, C18/ACN, Retention Time=3.08 minutes (M+H) 601.05.

(R)-3-((2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (48)

To a solution of crude(R)-3-((2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid, 138a, (0.11 g, 0.21 mmol) in CH₂Cl₂ was added triethylsilane (0.15mL, 0.94 mmol) followed by trifluoroacetic acid (0.15 mL, 1.95 mmol).After stirring the resulting solution at room temperature for 1 hour,the reaction mixture was kept below 5° C. overnight (refrigerator). Themixture was then allowed to warm to room temperature and kept at thattemperature for an additional 5 hours. The solution was diluted withtoluene and concentrated in vacuo. Trituration with Et₂O followed bypreparative HPLC purification provided 15 mg of the desired product asthe TFA salt. ¹H NMR indicated a 3 to 1 mixture of atropisomers: ¹H NMR(400 MHz, MeOD, major isomer) δ 8.63-8.45 (m, 2H), 7.96 (d, J=7.3 Hz,2H), 6.66 (d, J=7.3 Hz, 2H), 4.95 (d, J=10.6 Hz, 2H), 2.84 (dd, J=15.4,2.4 Hz, 2H), 2.44 (dd, J=15.9, 10.7 Hz, 2H), 0.98 (s, 9H); LCMS Gradient10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, RetentionTime=2.12 minutes (M+H) 359.02.

Preparation of Compound 42

Formation of (R)-ethyl3-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate(143a)

To a solution of racemic ethyl3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.40 g, 2.01 mmol) and2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.46 g, 2.41 mmol) in THF(20 mL) was added triethylamine (0.67 mL, 4.82 mmol). The reactionmixture was stirred at 90° C. in a pressure tube for 18 hours. Thereaction mixture was filtered and the resulting filtrate wasconcentrated in vacuo. The product was purified by silica gelchromatography (25% EtOAc/Hexanes) to afford 380 mg of the desiredproduct as a racemic mixture: ¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J=9.7Hz, 1H), 5.56 (d, J=8.9 Hz, 1H), 4.68 (td, J=9.6, 3.6 Hz, 1H), 4.07 (q,J=7.1 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46 (dd, J=14.8, 9.3 Hz,1H), 1.77-1.62 (m, 4H), 1.61-1.49 (m, 2H), 1.47-1.37 (m, 1H), 1.35-1.26(m, 1H), 1.19 (t, J=7.1 Hz, 3H), 1.01 (s, 3H); LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.81 minutes (M+H)354.98. The racemic mixture was submitted to SFC chiral separation togive the individual enantiomers, 143a and 143b. The (R)-enantiomer,143a, was taken forward into the next synthetic step.

Formation of (R)-ethyl3-(5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate(144a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.155 g, 0.373 mmol), racemic ethyl3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-3-(1-methylcyclopentyl)propanoate,143a, (0.120 g, 0.339 mmol) and K₃PO₄ (0.288 g, 1.357 mmol) in 2-methylTHF (10.0 mL) and H₂O (0.24 mL) was degassed under a stream of nitrogenfor 30 minutes. To the mixture was added X-phos (0.020 g, 0.041 mmol)and Pd₂(dba)₃ (0.008 g, 0.008 mmol). The reaction mixture was stirred at130° C. in a pressure tube for 45 minutes. The organic phase wasfiltered through a pad of celite and concentrated in vacuo. Theresulting crude material was purified by silica gel chromatography (30%EtOAc/Hexanes) to afford 150 mg of the desired product: ¹H NMR (400 MHz,CDCl₃) δ 8.67 (s, 1H), 8.44 (dt, J=15.3, 7.7 Hz, 1H), 8.37 (d, J=1.5 Hz,1H), 8.13 (t, J=7.6 Hz, 2H), 7.41 (d, J=10.3 Hz, 1H), 7.32 (d, J=7.5 Hz,2H), 5.38 (t, J=9.7 Hz, 1H), 4.89 (td, J=10.1, 3.3 Hz, 1H), 4.02-3.91(m, 2H), 2.74 (dd, J=15.1, 3.5 Hz, 1H), 2.52 (dd, J=15.1, 10.2 Hz, 1H),2.40 (s, 3H), 1.61 (ddt, J=32.0, 20.7, 7.7 Hz, 7H), 1.49-1.30 (m, 3H),1.27 (t, J=7.1 Hz, 3H), 1.08-0.97 (m, 3H). LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, Retention Time=4.22 min (M+H) 608.29.

Formation of (R)-methyl3-(5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate(145a)

To a solution of racemic ethyl3-(5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate,144a, (0.150 g, 0.247 mmol) in THF (20 mL) was added sodium methoxide(0.053 mL of 25% wt solution in MeOH, 0.247 mmol). The reaction mixturewas stirred at room temperature for 5 minutes. The reaction mixture wasdiluted with aqueous saturated NaHCO₃ solution and EtOAc. The organicphase was dried over MgSO₄, filtered and concentrated in vacuo. Theproduct was purified by silica gel chromatography (40% EtOAc/Hexanes) toafford 90 mg of the desired product as a mixture of ethyl and methylesters. The mixture was taken onto the next step without furtherpurification: ¹H NMR (400 MHz, CDCl₃) δ 10.18 (s, 1H), 8.65 (dd, J=9.6,2.5 Hz, 1H), 8.48 (d, J=2.8 Hz, 1H), 8.32 (s, 1H), 7.37 (t, J=14.1 Hz,1H), 5.38 (d, J=7.9 Hz, 1H), 5.02 (td, J=9.8, 3.5 Hz, 1H), 3.54 (s, 3H),2.80 (dt, J=15.8, 7.9 Hz, 1H), 2.57 (dd, J=14.9, 9.8 Hz, 1H), 1.80-1.57(m, 7H), 1.43 (ddd, J=24.5, 14.1, 6.0 Hz, 3H), 1.08 (s, 3H); LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=3.60 minutes (M+H) 440.26.

Formation of(R)-3-(5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoicacid (42)

To a solution of racemic methyl3-(5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate,145a, (0.090 g, 0.204 mmol) in THF (30 mL) was added a solution oflithium hydroxide (0.035 g, 0.819 mmol) in H₂O (10 mL). The reactionmixture was stirred at 70° C. overnight. The organic phase was removedunder reduced pressure and the resulting residue was purified bypreparatory HPLC. The appropriate HPLC fractions were extracted withEtOAc, and the solvent was removed under reduced pressure: ¹H NMR (400MHz, MeOD) δ 8.64 (dd, J=8.4, 2.4 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J=4.4Hz, 1H), 5.19 (d, J=8.7 Hz, 1H), 2.78 (qd, J=15.9, 6.6 Hz, 2H),1.85-1.57 (m, 6H), 1.48 (dd, J=11.8, 6.0 Hz, 1H), 1.36 (dt, J=12.0, 6.0Hz, 1H), 1.11 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=3.21 minutes (M+H) 426.25.

Preparation of Compounds 5, 6 and 12

Formation of (+/−)-ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-methylcyclopentyl)propanoate(147a)

To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.184 g, 1.100 mmol)and racemic ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.199g, 1.000 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine(0.307 mL, 2.200 mmol). The reaction mixture was stirred at 70° C. for 5hours. The mixture was filtered and the filtrate was concentrated invacuo. The resulting residue was purified via silica gel chromatography(25% EtOAc/Hexanes) to afford 180 mg of the desired product: ¹H NMR (400MHz, CDCl₃) δ 7.88 (d, J=2.7 Hz, 1H), 5.54 (d, J=9.2 Hz, 1H), 4.74-4.54(m, 1H), 4.08 (q, J=7.2 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46(dd, J=14.8, 9.3 Hz, 1H), 1.69 (dd, J=12.8, 8.8 Hz, 4H), 1.63-1.50 (m,2H), 1.46-1.38 (m, 1H), 1.37-1.23 (m, 1H), 1.23-1.14 (m, 3H), 1.00 (s,3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=3.54 minutes (M+H) 330.17.

Formation of (+/−)-ethyl3-(5-fluoro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclopentyl)propanoate(148a)

A solution of K₃PO₄ (0.464 g, 2.183 mmol), racemic ethyl3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3-(1-methylcyclopentyl)propanoate,147a, (0.180 g, 0.546 mmol) and5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine,135a, (303.4 mg, 0.6004 mmol) in 2-Methyl THF (3.240 mL) and H₂O (0.360mL) was degassed under a stream of nitrogen for 30 minutes. To thismixture was added X-phos (0.031 g, 0.066 mmol) and Pd₂(dba)₃ (0.013 g,0.014 mmol). The reaction mixture was stirred at 135° C. in a pressuretube for 1 hour. The organic phase was filtered through a pad of celiteand concentrated in vacuo. The resulting residue was purified by silicagel chromatography (30% EtOAc/Hexanes) to afford 240 mg of the desiredproduct: ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J=8.5, 2.7 Hz, 1H), 8.15(d, J=2.4 Hz, 2H), 7.27 (dd, J=11.0, 5.0 Hz, 15H), 5.38 (d, J=9.7 Hz,1H), 4.89 (dd, J=9.7, 6.0 Hz, 1H), 3.99 (q, J=7.1 Hz, 2H), 2.73 (dd,J=14.7, 3.8 Hz, 1H), 2.52 (dd, J=14.8, 9.4 Hz, 1H), 1.68 (dd, J=12.0,6.6 Hz, 2H), 1.64-1.52 (m, 4H), 1.47-1.36 (m, 1H), 1.30 (dt, J=14.3, 7.2Hz, 2H), 1.11-0.99 (m, 4H). LCMS Gradient 60-98%, formic acid, 7minutes, C18/can, Retention Time=3.24 minutes (M+H) 672.85.

Formation of (+/−)-ethyl3-(5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclopentyl)propanoate(149a)

To a solution of racemic ethyl3-[[5-fluoro-2-(5-fluoro-1-trityl-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclopentyl)propanoate,148a, (0.240 g, 0.357 mmol) in dichloromethane (20 mL) was addedtriethylsilane (0.285 mL, 1.784 mmol) followed by trifluoroacetic acid(0.275 mL, 3.567 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated in vacuoand the resulting crude residue was purified by silica gelchromatography (5% MeOH/CH₂Cl₂) to afford the desired product: ¹H NMR(400 MHz, CDCl₃) δ 11.80 (s, 2H), 8.59 (d, J=12.3 Hz, 2H), 8.48 (d,J=7.9 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 5.07 (s, 1H), 4.09 (q, J=7.0 Hz,2H), 2.97-2.59 (m, 2H), 1.70 (dd, J=27.7, 13.9 Hz, 6H), 1.57-1.33 (m,2H), 1.16 (dd, J=18.1, 11.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=2.97 minutes (M+H) 431.24.

Formation of(+/−)-3-(5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclopentyl)propanoicacid (12)

To a solution of racemic ethyl3-[[5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(1-methylcyclopentyl)propanoate,149a, (0.110 g, 0.256 mmol) in THF (30 mL) was added a solution oflithium hydroxide hydrate (0.043 g, 1.022 mmol) in H₂O (20 mL). Thereaction mixture was stirred at 70° C. overnight. The organic solventwas removed under reduced pressure and the remaining aqueous phase wasused directly in the purification via preparatory HPLC. The resultingHPLC fractions were extracted with EtOAc. The organic phase was driedover MgSO₄, filtered and the solvent was removed under reduced pressureto afford the desired product: ¹H NMR (400 MHz, MeOD) δ 8.64 (dd, J=8.4,2.4 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J=4.4 Hz, 1H), 5.19 (d, J=8.7 Hz,1H), 2.78 (qd, J=15.9, 6.6 Hz, 2H), 1.85-1.57 (m, 6H), 1.48 (dd, J=11.8,6.0 Hz, 1H), 1.36 (dt, J=12.0, 6.0 Hz, 1H), 1.11 (s, 3H). LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.37 min,(M+H) 403.22.

The following compounds can be prepared in a similar fashion as theprocedure described above for Compound 12:

(R)-3-((5-fluoro-2-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (5)

Compound 5 was synthesized in a manner similar to compound 12, startingwith compound 6a: ¹H NMR (400 MHz, d6-DMSO) δ 12.65 (s, 1H), 9.43 (s,1H), 9.15 (s, 1H), 8.44 (d, J=4.7 Hz, 1H), 8.41-8.29 (m, 2H), 3.93 (s,1H), 3.54 (s, 1H), 1.19 (d, J=20.0 Hz, 9H); LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, Retention Time=2.70 min, (M+H) 393.32.

(R)-3-((3,5-difluoro-6-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl)amino)-4,4-dimethylpentanoicacid (6)

Compound 6 was synthesized in a manner similar to compound 12, utilizing(R)-ethyl3-((6-bromo-3,5-difluoropyridin-2-yl)amino)-4,4-dimethylpentanoate asthe intermediate for the Suzuki coupling. (R)-ethyl3-((6-bromo-3,5-difluoropyridin-2-yl)amino)-4,4-dimethyl-pentanoate wasprepared in the same fashion as intermediate, 143a, utilizing2-bromo-3,5,6-trifluoropyridine as the starting material instead of2-chloro-5,6-difluoropyridine-3-carbonitrile: ¹H NMR (400 MHz, CDCl₃) δ8.31 (d, J=6.4 Hz, 1H), 8.06 (s, 1H), 7.06 (t, J=9.7 Hz, 1H), 4.58 (s,2H), 2.80 (d, J=13.2 Hz, 1H), 2.29 (dd, J=13.3, 8.7 Hz, 1H), 0.98 (s,9H).; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=2.92 min, (M+H)

(R)-3-((2-(5-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (97) and methylester (96)

Compounds 96 and 97 were synthesized in a manner similar to compound 12,starting with compound 6a: ¹H NMR (300 MHz, MeOD) for Compound 97: δ8.95 (d, J=2.3 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H),5.12 (dd, J=10.7, 2.9 Hz, 1H), 2.93 (dd, J=16.5, 2.9 Hz, 1H), 2.73 (dd,J=16.4, 10.7 Hz, 1H), 1.10 (s, 9H); LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=2.79 min, (M+H) 407.37.

Preparation of Compounds 54, 56 and 53

Formation of 4-(2-tert-butylhydrazinyl)-2-chloro-5-fluoropyrimidine(151a)

To a solution of 2,4-dichloro-5-fluoro-pyrimidine (1.84 g, 11.00 mmol)and tert-butylhydrazine hydrochloride (1.25 g, 10.00 mmol) in THF (50mL) and EtOH (5 mL) was added triethylamine (4.18 mL, 30.00 mmol). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was filtered to remove triethylamine HCl salt and the filtrateconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (EtOAc/Hexanes) to afford 1.7 g of the desired product:¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=2.8 Hz, 1H), 6.47 (s, 1H), 4.60 (d,J=5.8 Hz, 1H), 1.09 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=2.19 minutes (M+H) 218.81.

Formation of ethyl2-(1-tert-butyl-2-(2-chloro-5-fluoropyrimidin-4-yl)hydrazinyl)ethanoate(152a)

To a suspension of4-(2-tert-butylhydrazinyl)-2-chloro-5-fluoropyrimidine, 151a, (1.50 g,6.86 mmol) in acetonitrile (68 mL) was added 2-bromoethyl acetate (0.84mL, 7.55 mmol) and K₂CO₃ (2.28 g, 16.46 mmol). The reaction mixture wasstirred at room temperature overnight. The mixture was diluted intoEtOAc and brine. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (30% EtOAc/Hexanes) to afford 1 g of the desired product:¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=3.1 Hz, 1H), 4.16 (dt, J=7.1, 5.9Hz, 2H), 3.74 (s, 2H), 1.30-1.23 (m, 3H), 1.20 (s, 9H). LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.69minutes (M+H) 305.09.

Formation of ethyl2-(1-tert-butyl-2-(5-fluoro-2-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyl)ethanoate(154a)

Boronate ester, 153a, was prepared in same fashion as boronate ester,7a, (see Synthetic Scheme 4) using3-bromo-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine instead of3-bromo-5-fluoro-1H-pyrrolo[2,3-b]pyridine.

A solution of1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyrrolo[2,3-b]pyridine,153a, (0.551 g, 1.181 mmol), ethyl2-(1-tert-butyl-2-(2-chloro-5-fluoropyrimidin-4-yl)hydrazinyl)ethanoate,152a, (0.300 g, 0.984 mmol) and K₃PO₄ (0.627 g, 2.953 mmol) in2-MethylTHF (26 mL) and H₂O (5 mL) was degassed under a stream ofnitrogen for 45 minutes. To the reaction mixture was added X-phos (0.056g, 0.118 mmol) and Pd₂(dba)₃ (0.022 g, 0.025 mmol). The reaction mixturewas heated at 120° C. for 75 minutes. The aqueous phase was removed andthe organic phase was filtered through a pad of celite, concentrated invacuo and purified by silica gel chromatography (30% EtOAc/Hexanes) toafford 540 mg of the desired product: ¹H NMR (400 MHz, CDCl₃) δ 9.49 (s,1H), 8.71 (t, J=7.0 Hz, 1H), 8.63 (d, J=11.1 Hz, 1H), 8.16-8.11 (m, 3H),7.31 (d, J=8.2 Hz, 2H), 7.11 (d, J=21.4 Hz, 1H), 4.10 (dd, J=13.4, 6.3Hz, 2H), 3.79 (s, 2H), 2.39 (s, 3H), 1.24 (s, 9H), 1.17 (t, J=7.1 Hz,3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=4.18 minutes (M+H) 609.37.

Formation of ethyl2-(1-(tert-butyl)-2-(5-fluoro-2-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyl)acetate(155a)

To a solution of ethyl2-(1-tert-butyl-2-(5-fluoro-2-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyl)ethanoate,154a, (0.54 g, 0.89 mmol) in THF (20 mL) was added tetrabutylammoniumfluoride (1.78 mL of 1 M, 1.78 mmol). The reaction mixture was stirredat room temperature for 30 minutes. The reaction mixture was dilutedinto EtOAc and brine. The organic phase was dried over MgSO₄, filteredand concentrated in vacuo. The resulting residue was purified via silicagel chromatography (70% EtOAc/Hexanes) to afford 300 mg of the desiredproduct. ¹H NMR (400 MHz, CDCl₃) δ 10.59 (s, 1H), 9.55 (s, 1H), 8.66 (s,1H), 8.29 (d, J=2.2 Hz, 1H), 8.13 (dd, J=3.8, 1.5 Hz, 1H), 7.14 (s, 1H),4.20-4.04 (m, 2H), 3.85 (s, 2H), 1.28 (d, J=9.1 Hz, 9H), 1.19 (dt,J=7.1, 3.6 Hz, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, Retention Time=2.93 min, (M+H) 455.43.

Formation of2-(1-(tert-butyl)-2-(5-fluoro-2-(5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyl)aceticacid (54)

To a solution of ethyl2-[tert-butyl-[[5-fluoro-2-[5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]amino]acetate,155a, (0.200 g, 0.440 mmol) in THF (40 mL) was added a solution oflithium hydroxide hydrate (0.074 g, 1.760 mmol) in H₂O (4 mL). Thereaction mixture was stirred at room temperature overnight. The reactionmixture concentrated in vacuo to remove the THF. The remaining aqueousphase was diluted to 8 mL and the solution was used directly in apreparatory HPLC. The product precipitated when the fraction wasconcentrated on rotavaporator. The solid was filtered and dried indesiccator with P₂O₅ to afford 120 mg of the desired product: ¹H NMR(400 MHz, d6-DMSO) δ 12.65 (s, 1H), 12.41 (s, 1H), 9.28 (s, 1H), 8.86(s, 1H), 8.65 (s, 1H), 8.30 (d, J=3.5 Hz, 2H), 3.97-3.70 (m, 1H), 3.51(s, 1H), 1.18 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=2.92 min, (M+H) 427.40

The following compounds can be prepared in a similar fashion as theprocedure described above for Compound 54:

Formation of2-(1-(tert-butyl)-2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)hydrazinyl)aceticacid-TFA (trifluoro acetic acid) salt (56)

¹H NMR (400 MHz, d6-DMSO) δ 12.65 (s, 1H), 9.43 (s, 1H), 9.15 (s, 1H),8.44 (d, J=4.7 Hz, 1H), 8.41-8.29 (m, 2H), 3.93 (s, 1H), 3.54 (s, 1H),1.19 (d, J=20.0 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=2.70 min, (M+H) 393.32.

Formation of2-(1-(tert-butyl)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyl)aceticacid-TFA salt (53)

¹H NMR (400 MHz, d6-DMSO) δ 12.57 (s, 1H), 9.40 (s, 1H), 8.88 (s, 1H),8.40 (d, J=18.7 Hz, 2H), 8.34 (s, 1H), 3.93 (s, 1H), 3.52 (s, 1H), 1.20(s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=2.50 min, (M+H) 377.42.

Preparation of Compounds 7, 8, and 18

Formation of ethyl3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate(158a)

A solution of ethyl 3-amino-4,4-dimethyl-hexanoate, 27a, (0.24 g, 1.28mmol), 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.29 g, 1.53 mmol)and Et₃N (0.43 mL, 3.07 mmol) in acetonitrile (4.8 mL) was stirred at70° C. overnight. The reaction mixture was concentrated in vacuo andpurified by silica gel chromatography (10-40% EtOAc/Hexanes gradient) toprovide 205 mg of ethyl3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate;LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=3.75 minutes (M+H) 342.04.

Formation of ethyl3-[[5-cyano-3-fluoro-6-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-pyridyl]amino]-4,4-dimethyl-hexanoate(159a)

A solution of ethyl3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate,158a, (0.21 g, 0.600 mmol),5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.30 g, 0.72 mmol) and K₃PO₄ (0.51 g, 2.40 mmol) in 2-methyl THF(20.5 mL) and H₂O (2.7 mL) was degassed for 45 minutes and treated withX-phos (0.03 g, 0.07 mmol) and Pd₂(dba)₃ (0.01 g, 0.02 mmol). Thereaction vessel was sealed and heated to 125° C. for 90 minutes. Aftercooling to room temperature, the aqueous phase was removed and theorganic phase was filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient)to provide 270 mg of the desired product: ¹H NMR (400 MHz, CDCl₃) δ 8.69(s, 1H), 8.51 (dd, J=9.1, 2.7 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.15 (d,J=8.4 Hz, 2H), 7.41 (d, J=10.3 Hz, 1H), 7.33 (d, J=8.1 Hz, 2H),5.28-5.22 (m, 1H), 4.92 (td, J=10.4, 3.2 Hz, 1H), 4.03-3.91 (m, 2H),2.75 (dd, J=14.9, 3.5 Hz, 1H), 2.45 (dd, J=12.6, 8.2 Hz, 1H), 2.40 (s,J=4.7 Hz, 3H), 1.36 (q, J=7.4 Hz, 2H), 1.01 (t, J=7.1 Hz, 3H), 0.92 (d,J=8.8 Hz, 6H), 0.88 (t, J=7.5 Hz, 3H). LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=2.86 minutes (M+H) 596.02.

Formation of3-[[5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-pyridyl]amino]-4,4-dimethyl-hexanoicacid (18)

Ethyl3-[[5-cyano-3-fluoro-6-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-pyridyl]amino]-4,4-dimethyl-hexanoate,159a, (0.27 g, 0.45 mmol) was dissolved in THF (7 mL) and treated withLiOH (4.50 mL of 1 M, 4.50 mmol). The reaction mixture was heated to 70°C. for 10 hours. After cooling to room temperature, water (20 mL) andethyl acetate (20 mL) were added and the layers were separated. Theaqueous layer was brought to a neutral pH by addition of 1N HCl, and theresulting precipitate was collected by filtration, washed with water andconcentrated in vacuo to provide 77 mg of the desired product: ¹H NMR(400 MHz, DMSO-d₆) δ 12.37 (s, 1H), 12.12 (s, 1H), 8.75 (d, J=9.9 Hz,1H), 8.32 (s, 2H), 7.83 (d, J=11.4 Hz, 1H), 7.48 (d, J=9.5 Hz, 1H), 5.00(t, J=9.1 Hz, 1H), 2.71-2.54 (m, 2H), 1.30 (d, J=7.4 Hz, 2H), 0.80 (t,J=18.7 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, Retention Time=3.14 minutes (M+H) 414.31.

The following compounds can be prepared in a similar fashion as theprocedure described above for Compound 18:

Formation of(R)-3-(5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-4,4-dimethylpentanoicacid (7)

¹H NMR (400 MHz, MeOD) δ 8.81 (dd, J=9.8, 2.7 Hz, 1H), 8.36 (s, 1H),8.20 (s, 1H), 7.53 (d, J=11.0 Hz, 1H), 5.04 (d, J=8.7 Hz, 1H), 2.80 (dd,J=15.2, 2.5 Hz, 1H), 2.59 (dd, J=15.0, 11.0 Hz, 1H), 0.99 (s, 9H); LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=3.0 minutes (M+H) 400.39.

Formation of(R)-3-(5-cyano-3-fluoro-6-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoicacid (8)

¹H NMR (300 MHz, CDCl₃) δ 10.70 (s, 1H), 8.42 (dd, J=9.6, 2.6 Hz, 1H),8.05 (s, 1H), 7.73 (s, 1H), 7.40 (t, J=8.4 Hz, 1H), 5.32 (d, J=6.6 Hz,1H), 4.83 (t, J=9.4 Hz, 1H), 2.89 (d, J=5.3 Hz, 1H), 2.34 (dd, J=12.8,9.6 Hz, 1H), 1.92-1.37 (m, 8H), 1.32-1.24 (m, 1H), 1.20-1.06 (m, 3H);LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=3.27 minutes (M+H) 426.31.

Preparation of Compound 55

Formation of(+/−)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanamide(164a)

To a solution of racemic3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanoicacid, 163a, (0.50 g, 0.94 mmol) in 15 mL of THF was added HBTU (0.36 g,0.95 mmol). The reaction was stirred for 15 minutes and then ammonia gaswas bubbled through for 5 minutes. The reaction was allowed to stir for12 hours and then concentrated to dryness. The residue was redissolvedin 20 mL of MeOH and treated with 3 mL of 2N LiOH. The reaction waswarmed to 60° C. for 3 hours and then concentrated to dryness. Theresidue was purified by silica gel chromatography (EtOAc) to afford 250mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=1.78 minutes (M+H) 375.45.

Formation of(+/−)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanenitrile(165a)

A solution of racemic3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanamide,164a, (0.250 g, 0.668 mmol) in pyridine was cooled to 0° C. and treatedwith trifluoroacetic acid anhydride (0.278 mL, 2.003 mmol). After 2hours at 0° C., the reaction was concentrated to dryness and the residuewas purified by silica gel chromatography (EtOAc) to afford 150 mg ofdesired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, Retention Time=2.41 minutes (M+H) 357.47.

Formation of(+/−)-N-(3,3-dimethyl-1-(2H-tetrazol-5-yl)butan-2-yl)-5-fluoro-2-yl)-5-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine(55)

To a solution of racemic3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanenitrile,165a, (0.150 g, 0.420 mmol) in 10 mL of dioxane was addedazido-tributylstannane (0.221 g, 0.668 mmol). The reaction vessel wassealed and warmed to 130° C. for 12 hours. Upon cooling, the reactionwas concentrated to dryness and the resulting residue was purified bysilica gel chromatography to afford 48 mg of desired product: ¹H NMR(300.0 MHz, d6-DMSO) δ 12.23 (s, H), 8.49 (d, J=9.6 Hz, H), 8.26-8.05(m, H), 4.03 (d, J=7.1 Hz, H), 3.48-3.35 (m, H), 3.17 (s, H), 2.50 (s,H), 1.99 (s, H), 1.13 (dt, J=25.1, 8.0 Hz, H), 1.01 (s, H), 0.96 (s, H)and 0.87 (d, J=6.6 Hz, H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=1.94 minutes (M+H) 400.46.

Preparation of Compounds 60 and 61

Formation of (S)-tert-Butyl2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate(168a)

To a stirring suspension of(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutane-1-thiol,77a, (1.50 g, 5.69 mmol) and K₂CO₃ (2.36 g, 17.06 mmol) in acetone (15mL) was added tert-butyl bromoacetate (1.26 mL, 8.53 mmol). Thesuspension was stirred at room temperature for 18 hours. The resultingsolid was filtered, washed with acetone and the filtrate wasconcentrated under reduced pressure. The crude residue was purified bysilica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 1.6 gof the desired product as an off-white solid: LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, Retention Time=3.81 minutes (M+H)378.06.

Formation of (S)-tert-Butyl2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutyl-sulfonyl)ethanoate(169a)

Oxone (5.37 g, 8.73 mmol) was added to a solution of (S)-tert-Butyl2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate,168a, (1.10 g, 2.91 mmol) in methanol (50 mL) and water (20 mL) and thesolution was stirred 3 hours at room temperature. The solution wasconcentrated in vacuo to give a white residue that was dissolved inwater (100 mL). The aqueous layer was extracted with EtOAc (3×50 mL) andthe combined organic phases was dried (MgSO₄), filtered and concentratedin vacuo to afford 750 mg of the desired product as a white solid: LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=1.29 minutes (M+H) 410.19.

Formation of (S)-tert-Butyl2-(2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutylsulfonyl)ethanoate(170a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.76 g, 1.83 mmol), (S)-tert-Butyl2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutyl-sulfonyl)ethanoate,169a, (0.75 g, 1.83 mmol) and K₃PO₄ (0.93 g, 4.39 mmol) in 2-methyl THF(10 mL) and water (2 mL) was degassed under a stream of nitrogen for 30minutes. X-Phos (0.06 g, 0.12 mmol) and Pd₂(dba)₃ (0.03 g, 0.03 mmol)were added and the reaction mixture was heated at 115° C. in a pressurevial for 2.5 hours. The reaction mixture was cooled to room temperature,filtered and concentrated in vacuo. The residue was dissolved in EtOAc(50 mL) and washed with water. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified viasilica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 1.0 gof the desired product as a foamy solid: LCMS Gradient 60-98% ACN/water,0.9% formic acid, 7 minutes, C4, Retention Time=2.39 minutes (M+H)564.34.

Formation of(S)-2-(2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutylsulfonyl)ethanoicacid (60)

To a solution of (S)-tert-butyl2-(2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutylsulfonyl)ethanoate,170a, (1.00 g, 1.50 mmol) in THF (50 mL) was added NaOMe (1.30 mL of 25%solution in MeOH, 1.45 mmol). The yellow colored solution was stirred atroom temperature for 30 minutes and then the mixture was diluted withaqueous saturated NH₄Cl solution. The solvent was removed under reducedpressure and the residue was dissolved in water (50 mL). The aqueouslayer was extracted with EtOAc (3×50 mL) and dried (MgSO₄), filtered andconcentrated in vacuo. The product was purified by silica gelchromatography (0-10% MeOH/CH₂Cl₂ gradient) to afford 0.50 g of thedetosylated ester intermediate as a white solid.

The ester (0.50 g) was dissolved in CH₂Cl₂ (4 mL) and trifluoroaceticacid (2 mL) was added. The solution was heated at 50° C. for 2 hours.The solvent was evaporated under reduced pressure. The residue wasdiluted with water (10 mL) and the solution was neutralized with aqueoussaturated NaHCO₃ solution. The aqueous phase was extracted with EtOAc(3×10 mL), dried (MgSO₄), filtered and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography (0-15% MeOH/CH₂Cl₂gradient) to afford 204 mg of the desired product, 60, as a white solid:LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=2.01 minutes (M+H) 454.21.

The following compounds can be prepared in the same fashion using theprocedure described above:

(S)-2-(2-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylsulfonyl)ethanoicacid (61)

¹H NMR (300 MHz, MeOD) δ 8.95 (s, 1H), 8.29-8.14 (m, 2H), 8.08 (d, J=4.0Hz, 1H), 5.26 (m, 1H), 4.21 (d, J=15.3 Hz, 1H), 3.92 (dd, J=30.0, 14.5Hz, 2H), 3.77-3.57 (m, 1H), 1.10 (s, 9H); LCMS Gradient 60-98%ACN/water, 0.9% formic acid, 7 minutes, C4, Retention Time=2.23 minutes(M+H) 470.14.

Preparation of Compound 64

Formation oftert-butyl-((S)-2(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylsulfinyl)ethanoate(175a)

Oxone (1.04 g, 1.69 mmol) was added to a stirring solution of(S)-tert-Butyl2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate,168a, (0.53 g, 1.41 mmol) in methanol (20 mL). The solution was stirredfor 15 minutes at room temperature. The solution was concentrated togive white residue which was dissolved in water (50 mL). The aqueouslayer was extracted with EtOAc (3×25 mL) and the organic layer was dried(MgSO₄), filtered and concentrated in vacuo to give 540 mg of thedesired product as a white solid: LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=3.05 minutes (M+H) 394.28.

tert-Butyl2-((S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutylsulfinyl)ethanoate(176a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.66 g, 1.58 mmol),tert-butyl((S)-2(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylsulfinyl)ethanoate,175a, (0.50 g, 1.27 mmol) and K₃PO₄ (0.65 g, 3.05 mmol) in 2-methyl THF(10 mL) and water (2 mL) was degassed under a stream of nitrogen for 30minutes. X-Phos (0.04 g, 0.08 mmol) and Pd₂(dba)₃(0.02 g, 0.02 mmol)were added and the reaction mixture was heated at 115° C. in a pressurevial for 4 hours. The reaction mixture was cooled to room temperature,filtered and concentrated in vacuo. The residue was dissolved in EtOAc(50 mL) and washed with water. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 450mg of the desired product as a white foamy solid: LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.91 minutes (M+H)648.40.

2-((S)-2-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutylsulfinyl)ethanoicacid (64)

To a solution of tert-butyl2-((S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3,3-dimethylbutylsulfinyl)ethanoate,176a, (0.42 g, 0.64 mmol) in THF (10 mL) was added NaOMe (0.21 mL of 25%solution in MeOH, 0.96 mmol). The solution was stirred at roomtemperature for 30 minutes. Aqueous saturated NH₄Cl solution was addedand the solvent was removed under reduced pressure. The residue wasdissolved in water (20 mL) and the aqueous layer was extracted withEtOAc (3×20 mL). The combined organic phases were dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (0-15% MeOH/CH₂Cl₂ gradient) to afford 36 mg of thedesired product as a white solid: ¹H NMR (400 MHz, MeOD) δ 8.60-8.52 (m,1H), 8.46 (s, 1H), 8.32 (d, J=5.3 Hz, 2H), 5.16 (m, 2H), 4.00 (d, J=14.7Hz, 1H), 3.80 (d, J=14.7 Hz, 1H), 3.59 (d, J=13.9, 1H), 1.12 (s, 9H);LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=1.93 minutes (M+H) 438.25.

Preparation of Compounds 66, 67, 72, and 73

Formation of(4R)-4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-1,1,1-trifluoro-5,5-dimethylhexan-2-ol(180a) and (181a)

To a solution of(3R)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-4,4-dimethyl-pentanal(0.212 g, 0.817 mmol) and (trifluoromethyl)trimethylsilane (1.96 mL,0.980 mmol) in THF (20 mL) was added cesium fluoride (0.001 g, 0.008mmol). The reaction mixture was stirred at room temperature for 1 hour.The reaction mixture was diluted into brine and EtOAc. The organic phasewas dried over MgSO₄, filtered and concentrated in vacuo. The cruderesidue was purified via silica gel chromatography (EtOAc/Hexanes) toafford 190 mg of the silylated alcohol. This intermediate was dilutedwith dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was addedto the mixture. The reaction mixture was stirred at room temperature for30 minutes. The reaction mixture was concentrated in vacuo and theresulting residue was purified via silica gel chromatography (60%EtOAc/Hexanes) to afford 60 mg of diastereomer 180a and 100 mg ofdiastereomer 181a. Each diastereomer was taken on separately through theremaining synthetic sequence.

Diastereomer, 180a: ¹H NMR (400 MHz, CDCl₃) δ 7.93 (dd, J=43.4, 2.6 Hz,1H), 5.10 (d, J=8.9 Hz, 1H), 4.13 (dd, J=15.8, 5.8 Hz, 1H), 3.94-3.71(m, 1H), 2.05 (ddd, J=13.7, 9.2, 2.1 Hz, 1H), 1.64 (t, J=12.9 Hz, 1H),1.05 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, Retention Time=3.18 minutes (M+H) 330.42.

Diastereomer, 181a: ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J=2.7 Hz, 1H),5.30 (d, J=11.6 Hz, 1H), 4.22-4.07 (m, 2H), 2.19 (ddd, J=28.7, 15.3,13.4 Hz, 1H), 1.74-1.59 (m, 1H), 1.04 (s, 9H). LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.26 minutes (M+H)330.42.

Formation of(4R)-1,1,1-trifluoro-4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexan-2-ol(182a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.091 g, 0.218 mmol), 7a,(4R)-4-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-1,1,1-trifluoro-5,5-dimethyl-hexan-2-ol,180a, (0.060 g, 0.182 mmol) and K₃PO₄ (0.116 g, 0.546 mmol) in 2-methylTHF (5 mL) and H₂O (1.5 mL) was degassed under a stream of nitrogen for45 minutes. To the reaction mixture was added X-phos (0.010 g, 0.022mmol) and Pd₂(dba)₃ (0.004 g, 0.005 mmol). The reaction mixture wasstirred at 120° C. in a pressure tube for 2 hours. The aqueous phase wasremoved. The organic phase was filtered through a pad of celite andconcentrated in vacuo. The resulting residue was purified via silica gelchromatography (40% EtOAc/Hexanes) to afford 60 mg of the desiredproduct: ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 8.37 (dd, J=8.9, 2.8Hz, 1H), 8.24 (t, J=8.7 Hz, 1H), 8.16 (d, J=2.9 Hz, 1H), 8.00 (d, J=8.4Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 4.92 (t, J=7.8 Hz, 2H), 4.44 (t, J=10.3Hz, 1H), 4.06 (s, 1H), 2.34 (s, 3H), 2.13 (dt, J=13.6, 4.9 Hz, 1H), 1.66(dd, J=23.0, 9.3 Hz, 1H), 1.07 (d, J=8.4 Hz, 9H). LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, Retention Time=4.02 min (M+H)584.41.

The second diastereomeric alcohol, 181a, was also reacted in the samefashion to produce the diastereomeric Suzuki product. 184a: ¹H NMR (400MHz, CDCl₃) δ 8.53 (s, 1H), 8.47 (dt, J=11.5, 5.7 Hz, 1H), 8.30 (d,J=1.9 Hz, 1H), 8.11-8.06 (m, 1H), 7.29-7.24 (m, 1H), 5.30-5.21 (m, 1H),4.61 (d, J=4.1 Hz, 1H), 4.29-4.16 (m, 2H), 2.43-2.33 (m, 4H), 1.75-1.66(m, 1H), 1.09 (d, J=10.8 Hz, 9H). LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=4.02 minutes (M+H) 584.44.

Formation of(4R)-1,1,1-trifluoro-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexan-2-ol(66 and 67)

To a solution of(4R)-1,1,1-trifluoro-4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexan-2-ol,182a, (0.053 g, 0.091 mmol) was added NaOMe (0.019 g of 25% solution inMeOH, 0.091 mmol). The reaction mixture was stirred at room temperaturefor 5 minutes. The reaction mixture was diluted into EtOAc and aqueoussaturated NaHCO₃ solution. The organic phase was dried over MgSO₄,filtered and concentrated in vacuo. The crude residue was purified bysilica gel chromatography (EtOAc/Hexanes) to afford 26 mg of the desiredproduct, 66: ¹H NMR (400 MHz, CDCl₃) δ 9.40 (s, 1H), 8.47 (dd, J=9.3,2.7 Hz, 1H), 8.15 (s, 1H), 8.10 (d, J=2.7 Hz, 1H), 7.99 (d, J=2.8 Hz,1H), 5.54 (s, 1H), 4.84 (d, J=7.5 Hz, 1H), 4.23 (t, J=9.9 Hz, 1H), 3.91(s, 1H), 2.07-1.97 (m, 1H), 1.62 (t, J=13.0 Hz, 1H), 1.01 (s, 9H); LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=2.42 minutes (M+H) 430.44.

The second diastereomeric product, 67, was made by removal of thetosyl-protecting group on intermediate, 184a, using the followingprocedure:

To a solution of(4R)-1,1,1-trifluoro-4-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-5,5-dimethyl-hexan-2-ol,184a, (0.060 g, 0.103 mmol) in THF (5 mL) was added tetrabutylammoniumfluoride (0.411 mL of 1 M solution, 0.412 mmol) at room temperature. Thereaction mixture was stirred at room temperature for 30 minutes. Thereaction mixture was diluted into EtOAc and aqueous saturated NaHCO₃solution. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (50% EtOAc/Hexanes) to afford 30 mg of desired product.¹H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.49 (dd, J=9.3, 2.6 Hz, 1H),8.16 (s, 1H), 8.10 (d, J=2.6 Hz, 1H), 8.06 (d, J=3.0 Hz, 1H), 5.30 (d,J=15.0 Hz, 1H), 5.19-5.10 (m, 1H), 4.32-4.24 (m, 1H), 4.23-4.17 (m, 1H),2.37 (dt, J=14.9, 3.4 Hz, 1H), 1.85-1.71 (m, 2H), 1.09 (s, 9H); LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=2.37 minutes (M+H) 430.47.

The following two diastereomers can be prepared in a similar fashion asthe procedure described above:

(4R)-4-((5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexan-2-ol(72 and 73)

Diastereomer 72:

¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 8.60 (dd, J=9.4, 2.7 Hz, 1H),8.26 (s, 1H), 8.20 (d, J=2.6 Hz, 1H), 8.10 (d, J=3.2 Hz, 1H), 5.06 (t,J=12.3 Hz, 1H), 4.28 (dd, J=9.6, 7.2 Hz, 1H), 3.96 (d, J=5.7 Hz, 1H),2.71 (s, 1H), 1.97 (ddd, J=14.2, 5.8, 2.9 Hz, 1H), 1.66-1.58 (m, 1H),1.28 (dd, J=6.5, 5.5 Hz, 4H), 1.04 (d, J=10.1 Hz, 9H); LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=1.93minutes (M+H) 376.46.

Diastereomer 73:

¹H NMR (400 MHz, CDCl₃) δ 10.81 (s, 1H), 8.47 (dd, J=9.3, 2.7 Hz, 1H),8.14 (s, 1H), 8.05 (dd, J=8.4, 2.9 Hz, 2H), 4.95 (s, 1H), 4.81 (d, J=8.3Hz, 1H), 4.31-4.14 (m, 1H), 3.72 (dd, J=8.9, 6.0 Hz, 1H), 1.83-1.70 (m,1H), 1.48-1.32 (m, 1H), 1.24-1.11 (m, 4H), 0.98 (s, 9H); LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.01minutes (M+H) 376.46.

Preparation of Compounds 70 and 71

Formation of(R)-2-chloro-N-(2,2-dimethylhex-5-en-3-yl)-5-fluoropyrimidin-4-amine(188a)

To a solution of methyl(triphenyl)phosphonium bromide (0.983 g, 2.753mmol) in THF (40 mL) was added LiHMDS (2.753 mL of 1 M solution, 2.753mmol). The reaction mixture was stirred at room temperature for 1 hour.A solution of(3R)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-4,4-dimethyl-pentanal(0.550 g, 2.118 mmol) in THF (20 mL) was added to the reaction mixtureresulting in significant precipitate formation. The reaction mixture wasstirred at room temperature for 45 minutes. The reaction mixture wasdiluted into EtOAc and aqueous saturated NH₄Cl solution. The organicphase was separated, dried over MgSO₄, filtered and concentrated invacuo. The resulting residue was purified by silica gel chromatography(EtOAc/Hexanes) to afford 180 mg of desired product: ¹H NMR (400 MHz,CDCl₃) δ 7.80 (d, J=2.8 Hz, 1H), 5.76-5.60 (m, 1H), 5.05-4.91 (m, 2H),4.82 (t, J=22.1 Hz, 1H), 4.26-4.11 (m, 1H), 2.58-2.48 (m, 1H), 2.07-1.92(m, 1H), 0.94 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=3.60 minutes (M+H) 258.38.

Formation of(4R)-4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5,5-dimethylhexane-1,2-diol(189a) and (190a)

To a solution of(R)-2-chloro-N-(2,2-dimethylhex-5-en-3-yl)-5-fluoropyrimidin-4-amine,188a, (0.140 g, 0.543 mmol) in THF (10 mL) and H₂O (10 mL) was addedosmium tetraoxide (0.138 g, 0.014 mmol) and 4-methylmorpholine-4-oxide(0.085 mL, 0.815 mmol). The reaction mixture was stirred at roomtemperature for 2.5 hours. The mixture was diluted with aqueoussaturated Na₂S₂O₃. The resulting mixture was stirred for 20 minutes andextracted with EtOAc. The organic phase was dried over MgSO₄, filteredand concentrated in vacuo. The resulting residue was purified by silicagel chromatography (MeOH/CH₂Cl₂) to afford 90 mg of the firstdiastereomer, 189a, and 65 mg of the second diastereomer, 190a.

Diastereomer 189a:

¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=2.6 Hz, 1H), 5.00 (d, J=9.2 Hz,1H), 4.17 (s, 1H), 4.08-3.96 (m, 1H), 3.49 (dd, J=19.2, 8.4 Hz, 3H),2.15 (s, 1H), 1.74 (ddd, J=13.2, 10.8, 2.2 Hz, 1H), 1.27 (dd, J=19.3,7.0 Hz, 1H), 0.92 (d, J=10.5 Hz, 9H); LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=2.24 minutes (M+H) 292.36.

Diastereomer 190a:

¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J=2.7 Hz, 1H), 5.29 (d, J=8.9 Hz,1H), 4.12-4.02 (m, 1H), 3.74 (d, J=9.0 Hz, 2H), 3.50 (s, 1H), 3.22 (s,1H), 2.12 (s, 1H), 1.95 (dt, J=14.7, 4.2 Hz, 1H), 1.56 (ddd, J=14.8,9.2, 7.4 Hz, 1H), 0.99 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid,5 minutes, C18/ACN, Retention Time=2.24 minutes (M+H) 292.39.

Formation of(4R)-4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexane-1,2-diol(191a)

To a solution of(4R)-4-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-5,5-dimethyl-hexane-1,2-diol,189a, (0.090 g, 0.309 mmol),5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine(0.167 g, 0.401 mmol) and K₃PO₄ (0.196 g, 0.926 mmol) in 2-Methyl THF(15 mL) and H₂O (2 mL) was degassed under a stream of nitrogen for 45minutes. To the reaction mixture was added X-phos (0.018 g, 0.037 mmol)and Pd₂(dba)₃ (0.007 g, 0.008 mmol). The reaction mixture was stirred at120° C. in a pressure tube for 2 hours. The aqueous phase was removedand the organic phase was filtered through a pad of celite andconcentrated in vacuo. The resulting crude material was purified bysilica gel chromatography (60% EtOAc/Hexanes) to afford 140 mg of thedesired product, 191a: ¹H NMR (400 MHz, CDCl₃) δ 8.51 (dt, J=7.6, 3.8Hz, 1H), 8.48 (s, 1H), 8.32 (d, J=1.7 Hz, 1H), 8.12 (dd, J=7.2, 5.7 Hz,3H), 7.30 (d, J=8.1 Hz, 2H), 4.99 (d, J=10.1 Hz, 1H), 4.42-4.28 (m, 2H),3.72-3.47 (m, 3H), 2.40 (s, 3H), 2.19-2.09 (m, 1H), 1.97-1.83 (m, 1H),1.49-1.34 (m, 1H), 1.06 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid,5 minutes, C18/ACN, Retention Time=3.53 minutes (M+H) 546.49.

The second diastereomeric 1,2-diol, 190a, was also reacted in the samefashion to produce the diastereomeric Suzuki product. 193a: ¹H NMR (400MHz, CDCl₃) δ 8.56-8.49 (m, 2H), 8.32 (dd, J=2.8, 1.1 Hz, 1H), 8.15-8.02(m, 3H), 7.30 (d, J=9.2 Hz, 2H), 5.21-5.12 (m, 1H), 4.27 (td, J=9.7, 3.0Hz, 1H), 3.93-3.74 (m, 2H), 3.55 (d, J=7.7 Hz, 1H), 3.11 (s, 1H), 2.39(s, 3H), 2.01 (m, 1H), 1.65-1.50 (m, 1H), 1.05 (s, 9H). LCMS Gradient10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.54minutes (M+H) 546.49.

Formation of(4R)-4-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhexane-1,2-diol(70, 71)

To a solution of(4R)-4-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-5,5-dimethyl-hexane-1,2-diol,191a, (0.140 g, 0.257 mmol) in THF (10 mL) was added sodium methoxide(0.055 g of 25% w/w solution, 0.257 mmol). The reaction mixture wasstirred at room temperature for 5 minutes. The reaction mixture wasdiluted into EtOAc and aqueous saturated NaHCO₃ solution. The organicphase was dried over MgSO₄, filtered and concentrated in vacuo. Thecrude residue was purified via silica gel chromatography (MeOH/CH₂Cl₂)followed by preparative HPLC to afford 10 mg pure desired product: ¹HNMR (400 MHz, d6-DMSO) δ 8.61 (dd, J=9.9, 2.6 Hz, 1H), 8.26 (s, 1H),8.18 (s, 1H), 8.11 (d, J=4.1 Hz, 1H), 4.66 (d, J=10.4 Hz, 1H), 4.43 (s,1H), 4.29 (d, J=4.1 Hz, 1H), 4.04 (s, 1H), 3.35 (s, 1H), 3.26 (d, J=6.1Hz, 2H), 1.69 (t, J=12.3 Hz, 1H), 1.59-1.45 (m, 1H), 0.96 (s, 9H). LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=1.76 minutes (M+H) 392.46.

The second diastereomeric 1,2-diol, 193a, was also reacted in the samefashion to produce the diastereomeric final product: ¹H NMR (400 MHz,CDCl₃) δ 8.61 (dd, J=9.6, 2.7 Hz, 1H), 8.17 (s, 2H), 8.01 (d, J=4.1 Hz,1H), 4.53 (d, J=10.0 Hz, 1H), 3.75-3.56 (m, 2H), 3.48 (dd, J=11.0, 6.3Hz, 1H), 2.08-1.97 (m, 1H), 1.75 (dt, J=28.7, 9.4 Hz, 1H), 1.04 (s, 9H).LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=1.79 minutes (M+H) 392.46.

Preparation of Compounds 75, 76, 79, 85, 93, and 95

Formation of ethyl 3-oxo-3-(1-(trifluoromethyl)cyclopentyl)propanoate(195a)

To a solution of 1-(trifluoromethyl)cyclopentanecarboxylic acid (1.30 g,7.14 mmol) in dichloromethane (14 mL) was added carbonyl diimidazole(5.46 g, 33.68 mmol). After stirring 5 hours at room temperature, thereaction was concentrated in vacuo to a residue.

In another flask, 3-ethoxy-3-oxo-propanoate (Potassium Ion) (2.03 g,11.90 mmol) was mixed with dichloromagnesium (1.13 g, 11.90 mmol) andDMAP (72.65 mg, 0.59 mmol) in THF (23.13 mL) and acetonitrile (11.57mL). After 3 hours, the above crude solution in THF (10 mL) was added,followed by triethylamine (1.66 mL, 11.90 mmol). The reaction wasallowed to stir at 25° C. for 8 hours. The crude product was isolated byextracting into ethyl acetate (2×100 mL) vs 1N HCl (100 mL), dried oversodium sulfate and concentrated in vacuo to afford 1.0 g of the desiredproduct as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 12.58 (s, H), 5.32(s, H), 4.27-4.18 (m, 2H), 2.33-2.14 (m, 2H), 2.05-1.85 (m, 4H),1.77-1.69 (m, 2H) and 1.30 (td, J=7.1, 3.2 Hz, 3H) ppm.

Formation of (+/−)-ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-(trifluoromethyl)-cyclopentyl)propanoate(196a)

A solution of ethyl 3-oxo-3-(1-(trifluoromethyl)cyclopentyl)propanoate,195a, (0.500 g, 1.982 mmol) and ammonium acetate (0.458 g, 5.946 mmol)in EtOH (20 mL) was warmed to reflux for 3 hours. The crude reaction wasconcentrated in vacuo to a residue and redissolved in EtOAc (20 mL). Thenew mixture was cooled to 0° C., and acetic acid (0.338 mL, 5.946 mmol)and sodium cyanoborohydride (0.498 g, 7.928 mmol, 4 equiv) were added tothe mixture. The reaction was allowed to warm to room temperature andstirred overnight. The reaction was quenched with aqueous saturatedsodium bicarbonate solution (10 mL) and extracted with ethyl acetate(2×20 mL). The organic phase was concentrated in vacuo and redissolvedin EtOH (20 mL). To the solution was added2,4-dichloro-5-fluoro-pyrimidine (0.496 g, 2.973 mmol) andN,N-diisopropylethylamine base (2.0 mL). The reaction was refluxed for12 hours and then concentrated in vacuo. The residue was purified bysilica gel chromatography (EtOAc) yielding 84 mg of the desired productas a yellow oil: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, Retention Time=3.54 minutes (M+H) 384.40.

Formation of (+/−)-ethyl3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-(trifluoromethyl)cyclopentyl)propanoate(197a)

To a solution of racemic ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-(trifluoromethyl)cyclopentyl)propanoate,196a, (0.084 g, 0.219 mmol) in THF (10 mL) and water (1 mL) was added5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.137 g, 0.328 mmol) and potassium phosphate (0.140 g, 0.657 mmol).The resulting mixture was degassed under a stream of nitrogen for 10minutes. To the reaction was then added X-Phos (0.010 g, 0.021 mmol) andPd₂(dba)₃ (0.010 g, 0.011 mmol). The reaction was irradiated for 15minutes at 135° C. in a microwave. The resulting mixture wasconcentrated in vacuo to a brown oil which was purified by silica gelchromatography (EtOAc/CH₂Cl₂) to afford 80 mg of the desired product asa pale yellow solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, Retention Time=4.22 minutes (M+H) 638.42.

Formation of(+/−)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-(trifluoromethyl)cyclopentyl)propanoicacid (75)

To a solution of racemic ethyl3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-(trifluoromethyl)cyclopentyl)propanoate,197a, (0.080 g, 0.120 mmol) in THF (10 mL) was added lithium hydroxide(2 mL of 2N solution). The reaction was refluxed for 3 hours and cooledto room temperature. The non aqueous solvent was removed under reducedpressure and the aqueous layer was adjusted to pH 4. The aqueous layerwas extracted with ethyl acetate (2×20 mL). The combined organic phasesconcentrated in vacuo to afford 16 mg of the desired product as a paleyellow solid: ¹H NMR (300 MHz, d6-DMSO) δ 8.51 (s, H), 8.25-7.97 (m,2H), 7.58-7.42 (m, 2H), 7.12 (d, J=7.5 Hz, H), 4.35 (m, H), 2.85 (m, 2H)and 1.27-0.70 (m, 8H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=2.55 minutes (M+H) 456.45.

The following analogs can be prepared in a similar fashion as theprocedure described above Compound 75:

(+/−)-5,5,5-Trifluoro-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4,4-dimethylpentanoicacid (79)

¹H NMR (300 MHz, MeOD) δ 8.66 (d, J=8.9 Hz, H), 8.29 (s, H), 8.22-8.18(m, 2H), 4.16-4.06 (m, H), 2.97 (s, H), 2.92 (s, H), and 1.27-1.21 (m,6H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=2.22 minutes (M+H) 430.41.

(+/−)-5-Fluoro-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (76)

¹H NMR (300 MHz, MeOD) δ 8.70 (dd, J=9.7, 2.8 Hz, 1H), 8.15 (dd, J=6.1,4.0 Hz, 2H), 8.02 (d, J=4.1 Hz, 1H), 5.23 (dd, J=10.7, 3.1 Hz, 1H), 4.30(d, J=47.9 Hz, 2H), 3.63 (d, J=18.2 Hz, 1H), 3.31 (dt, J=3.3, 1.6 Hz,3H), 2.83 (dd, J=15.3, 3.3 Hz, 1H), 2.63 (dd, J=15.3, 10.8 Hz, 1H), 1.07(s, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,(M+H) 394.

(R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-methylcyclopropyl)propanoicacid (91)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 374.

(+/−)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(1-(trifluoromethyl)cyclopropyl)propanoicacid (93)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=2.37 minutes (M+H) 428.49.

(+/−)-3-(Bicyclo[2.2.1]heptan-1-yl)-3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)propanoicacid (95)

¹H NMR (400 MHz, CD₃OD) δ 8.62 (dd, J=9.3, 2.6 Hz, 1H), 8.48 (t, J=5.4Hz, 1H), 8.32 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 5.42 (dd, J=10.0, 3.4 Hz,1H), 2.84 (m, 2H), 2.18 (s, 1H), 1.65 (m, 4H), 1.39 (m, 6H); LCMSGradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RetentionTime=2.12 minutes (M+H) 414.28.

(+/−)-5-Fluoro-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4-(fluoromethyl)-4-methylpentanoicacid (84)

¹H NMR (300 MHz, MeOD) δ 8.67 (dd, J=9.6, 2.8 Hz, 1H), 8.16 (m, 2H),8.04 (d, J=4.0 Hz, 1H), 5.38 (dd, J=10.8, 3.2 Hz, 1H), 4.72-4.23 (m,4H), 2.86 (dd, J=15.5, 3.3 Hz, 1H), 2.70 (dd, J=15.5, 10.9 Hz, 1H), 1.15(s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,(M+H) 412.

(+/−)-3-((5-chloro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoicacid (85)

Carboxylic acid, 203, was prepared in same fashion as carboxylic acid,4, (see Synthetic Scheme 1) using5-chloro-3-(5-chloro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridineinstead of sulfoxide, 1: ¹H NMR (400 MHz, MeOD) δ 8.68 (dd, J=9.3, 2.7Hz, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 5.17 (dd, J=9.8, 3.5Hz, 1H), 2.87 (m, 2H), 1.06 (s, 9H); LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=2.1 minutes (M+H) 383.38.

Preparation of Compounds 77, 78, 83, 86, and 94

Formation of (+/−)-ethyl-3-amino-3-(1-methylcyclohexyl)propanoate (205a)

A solution of 1-methylcyclohexanecarbaldehyde (2.75 g, 21.79 mmol),malonic acid (2.27 g, 21.79 mmol) and ammonium acetate (3.36 g, 43.58mmol) in absolute ethanol (5 mL) was heated at reflux for 4 hours. Thesolid was filtered and washed with ethanol (10 mL). The filtrate wasconcentrated in vacuo to give a thick oil that was diluted with CH₂Cl₂(50 mL). The precipitated solid was filtered and the filtrate wasconcentrated in vacuo to afford 4.3 grams of a yellow oil. Concentratedsulfuric acid (1.16 mL, 21.79 mmol) was added to a solution of the crudematerial in absolute ethanol (25 mL) and the mixture was refluxed for 12hours. The solution was cooled to room temperature and concentrated invacuo to give a thick oil. Water (10 mL) was added and the solution wasneutralized with 2N NaOH. The aqueous layer was extracted with EtOAc(3×25 mL), dried (MgSO₄), filtered and concentrated in vacuo to afford2.4 grams of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=1.54 minutes (M+H) 214.14.

Formation of (+/−)-ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoate(206a)

A mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.83 g, 85.33 mmol),racemic ethyl-3-amino-3-(1-methylcyclohexyl)propanoate, 205a, (2.34 g,11.0 mmol) and N,N-diisopropylethylamine (4.79 g, 27.50 mmol) in THF (40mL) and methanol (10 mL) was heated at 95° C. for 3 hours. The solutionwas cooled to room temperature and the solvent was evaporated underreduced pressure. The crude residue was purified by silica gelchromatography (0-60% EtOAc/Hexanes gradient) to afford 620 mg of thedesired product as a white foamy solid: ¹H NMR (400 MHz, CDCl₃) δ 7.80(d, J=2.6 Hz, 1H), 5.37 (m, 1H), 4.59 (m, 1H), 4.00 (q, 7.2 Hz, 2H),2.62 (dd, J=14.7, 3.8 Hz, 1H), 1.67 (m, 1H), 1.17 (m, 10H), 1.10 (t,J=7.1 Hz, 3H), 0.85 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5minutes, C18/ACN, Retention Time=3.69 minutes (M+H) 344.39.

Formation of (+/−)-ethyl3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)-3-(1-methylcyclohexyl)propanoate(207a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.51 g, 1.22 mmol), racemic ethyl3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoate,206a, (0.35 g, 1.02 mmol) and K₃PO₄ (0.52 g, 2.44 mmol) in 2-methyl THF(8 mL) and water (2 mL) was degassed under a stream of nitrogen for 30minutes. X-Phos (0.03 g, 0.07 mmol) and Pd₂(dba)₃ (0.02 g, 0.02 mmol)were added and the resulting mixture was heated at 115° C. in a pressurevial for 4 hours. The reaction mixture was cooled to room temperature,filtered and concentrated in vacuo. The residue was dissolved in EtOAc(50 mL) and washed with water. The organic layer was dried (MgSO₄),filtered and concentrated in vacuo. The crude residue was purified viasilica gel chromatography (0-35% EtOAc/Hexanes gradient) to afford 486mg of the desired product as a white solid: ¹H NMR (400 MHz, CDCl₃) δ8.50 (m, 1H), 8.48 (s, 1H), 8.24 (d, J=1.7 Hz, 1H), 8.01 (m, 3H), 7.20(m, 2H), 5.12 (m, 1H), 4.88 (m, 1H), 3.89 (q, J=7.4 Hz, 2H), 2.71 (dd,J=14.5, 3.8 Hz, 1H), 2.39 ? 2.32 (m, 1H), 2.31 (s, 3H), 1.60-1.32 (m10H), 0.95 (t, J=7.4 3H). 0.87 (s, 3H); LCMS Gradient 60-98%, 0.1%formic acid, 7 minutes, C18/ACN, Retention Time=2.81 minutes (M+H)599.19.

Formation of (+/−)-ethyl3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoate(77)

To a solution of ethyl3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4ylamino)-3-(1-methylcyclohexyl)propanoate,207a, (0.49 mg, 0.81 mmol) in CH₃CN (3 mL) was added HCl (2.0 mL of 4Msolution in dioxane, 8.1 mmol). The solution was heated at 70° C. for 3hours and then cooled to room temperature. The solvent was removed underreduced pressure and the product was neutralized with aqueous saturatedNaHCO₃ solution. The precipitate was extracted with EtOAc (3×10 mL). Thesolvent was dried (MgSO₄), filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (0-70% EtOAc/Hexanesgradient) to afford 230 mg of the desired product as an off-white solid:¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 1H), 8.58 (dd, J=9.3, 2.5 Hz, 1H),8.18 (s, 2H), 8.00 (d, J=2.7 Hz, 1H), 5.13 (brs, 1H), 4.95 (t, J=8.2 Hz,1H), 3.84 (m, 2H), 2.72 (m, 1H), 2.38 (m, 1H), 1.67-1.15 (m, 10H), 0.94(m, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=2.77 minutes (M+H) 444.36.

3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoicacid (78)

LiOH (0.118 mg, 4.927 mmol) was added to a solution of ethyl3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)-propanoate,77, (0.23 g, 0.49 mmol) in water (5 mL) and THF (5 mL). The solution wasstirred at 95° C. for 18 hours and then cooled to room temperature. Thesolvent was removed under reduced pressure. The residue was diluted withwater (10 mL) and neutralized with 2N HCl. The resulting precipitate wasextracted with EtOAc (3×10 mL). The organic phase was dried (MgSO₄),filtered and concentrated in vacuo to afford 210 mg of the desiredproduct as an off-white solid: ¹H NMR (400 MHz, CD₃OD) δ 8.78 (dd,J=9.7, 2.7 Hz, 1H), 8.16 (s, 2H), 7.99 (d, J=4.1 Hz, 1H), 5.20 (d, J=9.9Hz, 1H), 2.86-2.69 (m, 1H), 2.53 (dd, J=14.7, 11.0 Hz, 1H), 1.76-1.56(m, 2H), 1.53 (m, 4H), 1.29 (m, 4H), 1.02 (s, 3H); LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.20 minutes (M+H)416.27.

(+/−)-3-(2-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoicacid (83)

Compound 83 was synthesized in a manner similar to3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoicacid, 78, using5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridineinstead of boronate ester, 7a: ¹H NMR (400 MHz, MeOD) δ 9.05 (d, J=2.1Hz, 1H), 8.39-8.24 (m, 2H), 8.16 (d, J=4.9 Hz, 1H), 5.23 (d, J=10.4 Hz,1H), 2.86 (d, J=15.6 Hz, 1H), 2.65 (m, 1H), 1.58 (m, 7H), 1.37 (m, 3H),1.05 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes,C18/ACN, Retention Time=2.37 minutes (M+H) 442.36.

(+/−)-3-(1-Adamantyl)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]propionicacid (86)

Compound 86 was synthesized in a manner similar to3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(1-methylcyclohexyl)propanoicacid, 78, using adamantine-1-carbaldehyde as the starting material: ¹HNMR (400 MHz, CD₃OD) δ 8.75 (dd, J=9.7, 2.7 Hz, 1H), 8.18 (s, 2H), 8.00(d, J=4.2 Hz, 1H), 2.81 (dd, J=15.2, 3.1 Hz, 1H), 2.55 (dd, J=15.2, 10.8Hz, 1H), 2.00 (m, 3H), 1.82-1.49 (m, 12H); LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, Retention Time=2.40 minutes (M+H)454.34.

(+/−)-3-(1-Adamantyl)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]propanoicacid (94)

Compound 94 was synthesized in a manner similar to3-(1-Adamantyl)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]propionicacid, 86, using5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridineinstead of boronate ester, 7a: ¹H NMR (400 MHz, CD₃OD) δ 9.02 (d, J=2.3Hz, 1H), 8.40-8.24 (m, 2H), 8.18 (d, J=5.0 Hz, 1H), 4.91 (d, J=11.6 Hz,1H), 2.88 (dd, J=16.0, 2.8 Hz, 1H), 2.65 (dd, J=15.9, 11.0 Hz, 1H), 2.01(s, 3H), 1.77 (dd, J=27.9, 11.9 Hz, 12H); LCMS Gradient 10-90%, 0.1%formic acid, 5 minutes, C18/ACN, Retention Time=2.60 minutes (M+H)470.27.

Preparation of Compound 68

Formation of(S)—N-(1-azido-3,3-dimethylbutan-2-yl)-2-chloro-5-fluoropyrimidin-4-amine(216a)

A mixture of(S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutylmethanesulfonate, 75a, (2.37 g, 7.26 mmol) and sodium azide (1.89 g,29.07 mmol) in DMF (50 mL) was heated at 70° C. for 6 hours. Thereaction mixture was cooled to room temperature and poured into water.The aqueous phase was extracted with EtOAc (2×25 mL), dried (MgSO₄),filtered and concentrated in vacuo. The crude product was purified viasilica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 1.2 gof the desired product as a white crystalline solid: ¹H NMR (400 MHz,CDCl₃) δ 7.86 (dd, J=2.6, 1.1 Hz, 1H), 5.07 (m, 1H), 4.32-4.09 (m, 1H),3.60 (dd, J=12.8, 3.9 Hz, 1H), 3.34 (dd, J=12.8, 7.6 Hz, 1H), 0.96 (m,9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN,Retention Time=3.28 minutes (M+H) 273.14.

Formation of(S)-(1-(2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol(217a)

A mixture of prop-2-yn-1-ol (0.22 g, 3.85 mmol) and(S)—N-(1-azido-3,3-dimethylbutan-2-yl)-2-chloro-5-fluoropyrimidin-4-amine,216a, (0.21 g, 0.77 mmol) in THF (4 mL) and toluene (4 mL) was heated ina pressure vial at 120° C. for 8 hours. The reaction mixture was cooledto room temperature and concentrated under reduced pressure. The crudeproduct which contained two regioisomers was purified by silica gelchromatography (0-5% MeOH/CH₂Cl₂ gradient) to afford 100 mg of desiredregioisomer, 217a, as well as 70 mg of the minor regioisomer(5-hydroxymethyl triazole).

4-Hydroxymethyl triazole regioisomer 217a: ¹H NMR (400 MHz, CDCl₃) δ7.71 (d, J=2.6 Hz, 1H), 7.19 (s, 1H), 5.31-5.16 (m, 1H), 4.86 (m, 1H),4.79-4.60 (m, 2H), 4.44 (m, 1H), 1.07 (s, 9H); LCMS Gradient 10-90%,0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.26 minutes (M+H)329.31.

Formation of(S)-(1-(2-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol(218a)

A solution of5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine,7a, (0.158 g, 0.380 mmol),(S)-(1-(2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol,217a, (0.100 g, 0.304 mmol) and K₃PO₄ (0.520 g, 2.440 mmol) in 2-methylTHF (8 mL) and water (2 mL) was degassed under a stream of nitrogen for30 minutes. X-Phos (0.008 g, 0.018 mmol) and Pd₂(dba)₃ (0.006 g, 0.006mmol) were added and the reaction mixture was heated at 115° C. in apressure vial for 4 hours. The reaction mixture was cooled to roomtemperature and filtered. The filtrate was concentrated in vacuo. Theresidue was dissolved in EtOAc (50 mL) and washed with water. Theorganic layer was dried (MgSO₄), filtered concentrated in vacuo. Thecrude residue was purified via silica gel chromatography (0-70%EtOAc/Hexanes gradient) to afford 120 mg of the desired product as awhite foamy solid: ¹H NMR (400 MHz, CDCl₃) δ 8.37 (s, 1H), 8.33 (s, 1H),8.21 (s, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.90 (d, J=3.0 Hz, 1H), 5.37 (m,1H), 4.92 ? 4.83 (m, 1H), 4.78-4.69 (m, 2H), 4.44 (dd, J=13.9, 11.3 Hz,1H), 2.32 (s, 3H), 1.11 (s, 9H); LCMS Gradient 60-98%, 0.1% formic acid,7 minutes, C18/ACN, Retention Time=1.29 minutes (M+H) 583.33

Formation of(S)-(1-(2-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol(68)

To a solution of(S)-(1-(2-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazol-4-yl)methanol,218a, (0.11 g, 0.19 mmol) in THF (5 mL) was added NaOMe (0.17 mL of 25%solution in MeOH, 0.75 mmol). After stirring the reaction mixture atroom temperature for 30 minutes, the mixture was diluted into aqueoussaturated NH₄Cl solution (5 mL) and EtOAc (10 mL). The organic layer wasseparated, dried (MgSO₄), filtered concentrated in vacuo. The crudeproduct was purified by silica gel chromatography (0-10% MeOH/CH₂Cl₂) toafford 41 mg of the desired product as an off-white solid: ¹H NMR (400MHz, CD₃OD) δ 8.51 (d, J=8.0 Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.93(d, J=3.5 Hz, 1H), 7.38 (s, 1H), 5.08 (m, 1H), 5.00-4.90 (m, 1H), 4.74(s, 2H), 4.60 (m, 1H), 1.2 (s, 9H); LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time=1.90 minutes (M+H) 429.26.

Example 2 Influenza Antiviral Assay

Antiviral assays were performed using two cell-based methods:

A 384-well microtiter plate modification of the standard cytopathiceffect (CPE) assay method was developed, similar to that of Noah, et al.(Antiviral Res. 73:50-60, 2006). Briefly, MDCK cells were incubated withtest compounds and influenza A virus (A/PR/8/34), at a low multiplicityof infection (approximate MOI=0.005), for 72 hours at 37° C., and cellviability was measured using ATP detection (CellTiter Glo, PromegaInc.). Control wells containing cells and virus show cell death whilewells containing cells, virus, and active antiviral compounds show cellsurvival (cell protection). Different concentrations of test compoundswere evaluated, in quadruplicate, for example, over a range fromapproximately 20 μM to 1 nM. Dose-response curves were prepared usingstandard 4-parameter curve fitting methods, and the concentration oftest compound resulting in 50% cell protection, or cell survivalequivalent to 50% of the uninfected wells, was reported as the IC₅₀.

A second cell-based antiviral assay was developed that depends on themultiplication of virus-specific RNA molecules in the infected cells,with RNA levels being directly measured using the branched-chain DNA(bDNA), hybridization method (Wagaman et al, J. Virol Meth, 105:105-114,2002). In this assay, cells are initially infected in wells of a 96-wellmicrotiter plate, the virus is allowed to replicate in the infectedcells and spread to additional rounds of cells, then the cells are lysedand viral RNA content is measured. This assay is stopped earlier thatthe CPE assay, usually after 18-36 hours, while all the target cells arestill viable. Viral RNA is quantitated by hybridization of well lysatesto specific oligonucleotide probes fixed to wells of an assay plate,then amplification of the signal by hybridization with additional probeslinked to a reporter enzyme, according to the kit manufacturer'sinstructions (Quantigene 1.0, Panomics, Inc.). Minus-strand viral RNA ismeasured using probes designed for the consensus type A hemagglutinationgene. Control wells containing cells and virus were used to define the100% viral replication level, and dose-response curves for antiviraltest compounds were analyzed using 4-parameter curve fitting methods.The concentration of test compound resulting in viral RNA levels equalto that of 50% of the control wells were reported as EC₅₀.

Virus and Cell culture methods: Madin-Darby Canine Kidney cells (CCL-34American Type Culture Collection) were maintained in Dulbecco's ModifiedEagle Medium (DMEM) supplemented with 2 mM L-glutamine, 1,000 U/mlpenicillin, 1,000 ug/ml streptomycin, 10 mM HEPES, and 10% fetal bovinemedium. For the CPE assay, the day before the assay, cells weresuspended by trypsinization and 10,000 cells per well were distributedto wells of a 384 well plate in 50 μl. On the day of the assay, adherentcells were washed with three changes of DMEM containing 1 ug/mlTPCK-treated trypsin, without fetal bovine serum. Assays were initiatedwith the addition of 30 TCID₅₀ of virus and test compound, in mediumcontaining 1 g/ml TPCK-treated trypsin, in a final volume of 50 μl.Plates were incubated for 72 hours at 37° C. in a humidified, 5% CO₂atmosphere. Alternatively, cells were grown in DMEM+fetal bovine serumas above, but on the day of the assay they were trypsinized, washed 2times and suspended in serum-free EX-Cell MDCK cell medium (SAFCBiosciences, Lenexa, Kans.) and plated into wells at 20,000 cells perwell. These wells were then used for assay after 5 hours of incubation,without the need for washing.

Influenza virus, strain A/PR/8/34 (tissue culture adapted) was obtainedfrom ATCC (VR-1469). Low-passage virus stocks were prepared in MDCKcells using standard methods (WHO Manual on Animal Influenza Diagnosisand Surveillance, 2002), and TCID₅₀ measurements were performed bytesting serial dilutions on MDCK cells in the 384-well CPE assay format,above, and calculating results using the Karber method.

Mean IC₅₀ values (mean all) for certain specific compounds aresummarized in Table 1:

A: IC₅₀ (mean all)<0.3 μM;

B 0.3 μM≦IC₅₀ (mean all)≦3.3 μM;

C IC₅₀ (mean all)>3.3 μM.

Mean EC₅₀ values (mean all) for certain compounds are also summarized inTable 1:

A: EC₅₀ (mean all)<0.3 μM;

B 0.3 μM≦EC₅₀ (mean all)≦3.3 μM;

C EC₅₀ (mean all)>3.3 μM.

Mean EC₉₉ values (mean all) for certain compounds are also summarized inTable 1:

A: EC₉₉ (mean all)<0.3 M;

B 0.3 M≦EC₉₉ (mean all)≦3.3 M;

C EC₉₉ (mean all)>3.3 μM.

Some exemplary data are as follows: Compound 1: IC₅₀=0.006 M, EC₅₀=0.009M, EC₉₉=0.0094 M; Compound 2: IC₅₀=0.004 M, EC₅₀=0.009 M, EC₉₉=0.0063 M;Compound 6: IC₅₀=0.004 M, EC₅₀=0.015 M, EC₉₉=0.082 M; Compound 69:IC₅₀=2.31 M, EC₅₀=0.8 μM, EC₉₉=8.4 μM; Compound 76: IC₅₀=0.423 M,EC₅₀=0.25 M, EC₉₉=1.4 μM.

For comparison purposes, some compounds disclosed in WO2005/095400 werealso tested against influenza virus using the bDNA and MDCK cellprotection assays described above, and their mean IC₅₀, EC₅₀, and EC₉₉values are summarized in Table 2.

TABLE 1 IC₅₀, EC₅₀, NMR and LCMS Data of Compounds of Invention. MDCKbDNA bDNA Compound IC50 EC50 EC99 LCMS nos. (uM) (uM) (uM) NMR M + 1 RT 1 A A A 12.25 (s, 1H): 12.0 (bs, 1H): 8.8 (s, 392.21 2.07 1H): 8.3 (s,1H): 8.25 (s, 1H); 8.1 (s, 1H): 7.45 (d, 1H); 4.75 (t, 1H); 2.5 (m, 2H),1.0 (s, 9H).  2 A A A 12.25 (s, 1H): 12.0 (bs, 1H): 8.6 (d, 376.21 1.921H): 8.3 (s, 1H): 8.2 (s, 1H); 8.15 (s, 1H): 7.45 (d, 1H); 4.8 (t, 1H);2.5 (m, 2H), 1.0 (s, 9H).  3 B B C 392.21 2.06  4 C C C 376.21 1.93  5 AA A 1H NMR (300 MHz, MeOD) d 8.60 (d, 377.24 2.17 J = 7.7 Hz, 2H), 8.33(s, 1H), 5.08 (t, J = 17.2 Hz, 1H), 2.93 (dd, J = 16.3, 2.8 Hz, 1H),2.73 (dd, J = 16.3, 10.6 Hz, 1H), 1.08 (s, 9H).  6 A A A 1H NMR (400MHz, CDCl3) d 8.31 (d, 394.19 2.92 J = 6.4 Hz, 1H), 8.06 (s, 1H), 7.06(t, J = 9.7 Hz, 1H), 4.58 (s, 2H), 2.80 (d, J = 13.2 Hz, 1H), 2.29 (dd,J = 13.3, 8.7 Hz, 1H), 0.98 (s, 9H).  7 A A A 1H NMR (300 MHz, MeOD) ?400.27 2.99 8.86 (dd, J = 9.8, 2.8 Hz, 1H), 8.37 (s, 1H), 8.26-8.14 (m,1H), 7.53 (d, J = 11.0 Hz, 1H), 5.04 (dd, J = 11.0, 2.9 Hz, 1H), 2.81(dd, J = 15.4, 3.0 Hz, 1H), 2.60 (dd, J = 15.4, 11.0 Hz, 1H), 0.99 (s,9H).  8 A A A 401.94 2.1 (diastereomer of Compound 15)  9 A A A 390.232.04 10 A A A 1H NMR (400 MHz, MeOD) ? 8.60 (s, 428 2.02 1H), 8.44 (s,1H), 8.23 (d, J = 5.3 Hz, 1H), 8.16 (s, 1H), 5.15 (m, 1H), 3.39 (d, J =8 Hz, 2H), 1.08 (s 9H). 11 A A A 1H NMR (400 MHz, MeOD) ? 8.44 (s,412.13 1.91 1H), 8.34 (dd, J = 9.2, 2.6 Hz, 1H), 8.22 (d, J = 5.7 Hz,1H), 8.13 (s, 1H), 5.16 (d, J = 4.1 Hz, 1H), 3.46-3.33 (m, 3H), 1.10 (d,J = 19.9 Hz, 10H). 12 A A A 1H NMR (400 MHz, MeOD) ? 403.22 2.37 8.64(dd, J = 8.4, 2.4 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 5.19(d, J = 8.7 Hz, 1H), 2.78 (qd, J = 15.9, 6.6 Hz, 2H), 1.85-1.57 (m, 6H),1.48 (dd, J = 11.8, 6.0 Hz, 1H), 1.36 (dt, J = 12.0, 6.0 Hz, 1H), 1.11(s, 3H). 13 A A A 1H NMR (400 MHz, MeOD) ? 426.25 3.21 8.64 (dd, J =8.4, 2.4 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J = 4.4 Hz, 1H), 5.19 (d, J =8.7 Hz, 1H), 2.78 (qd, J = 15.9, 6.6 Hz, 2H), 1.85-1.57 (m, 6H), 1.48(dd, J = 11.8, 6.0 Hz, 1H), 1.36 (dt, J = 12.0, 6.0 Hz, 1H), 1.11 (s,3H). 14 A A A 402.32 2.13 15 B B C 402.38 2.12 (diastereomer of Compound8) 16 A A A 390.35 2.03 17 B B C 389.97 2.03 18 A A A 1H NMR (400 MHz,DMSO) ? 414.31 3.14 12.37 (s, 1H), 12.12 (s, 1H), 8.75 (d, J = 9.9 Hz,1H), 8.32 (s, 2H), 7.83 (d, J = 11.4 Hz, 1H), 7.48 (d, J = 9.5 Hz, 1H),5.00 (t, J = 9.1 Hz, 1H), 2.71-2.54 (m, 2H), 1.30 (d, J = 7.4 Hz, 2H),0.80 (t, J = 18.7 Hz, 9H). 19 A A A 1H NMR (400 MHz, CDCl3) ? 9.75 (s,425.3 1.98 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.94 (s, 1H), 7.73 (s, 2H),7.67 (brs, 1H), 4.93-4.78 (m, 2H), 3.08 (m, 1H), 2.76 (s, 3H), 0.99 (m,9H). 20 A A A 1H NMR (400 MHz, DMSO) ? 390.06 2.14 12.23 (s, 1H), 11.93(s, 1H), 8.48 (d, J = 9.9 Hz, 1H), 8.33-8.07 (m, 3H), 7.18 (d, J = 9.3Hz, 1H), 4.39 (t, J = 10.2 Hz, 1H), 2.38-2.07 (m, 2H), 1.99-1.92 (m,1H), 1.80-1.64 (m, 1H), 1.00 (d, J = 20.2 Hz, 9H). 21 A A A 1H NMR (400MHz, MeOD) ? 451.14 2.2 8.68 (dd, J = 9.6, 2.5 Hz, 1H), 8.24-8.11 (m,2H), 8.03 (d, J = 3.8 Hz, 1H), 5.12 (d, J = 8.5 Hz, 1H), 3.48 (d, J =9.2 Hz, 2H), 2.60-2.47 (m, 1H), 0.68-0.48 (m, 4H). 22 A A B 1H NMR (400MHz, MeOD) ? 8.65 (d, 411 1.96 J = 9.3, 1H), 8.47 (s, 1H), 8.34 (m,,2H), 5.28 (d, J = 10.4 Hz, 1H), 3.55 (dt, J = 14.5, 13.0 Hz, 2H),1.20-1.03 (m, 9H). 23 B B C 1H NMR (400 MHz, DMSO) ? 419.08 2.41 12.23(s, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.32-8.06 (m, 3H), 7.18 (d, J = 9.6Hz, 1H), 4.36 (t, J = 10.4 Hz, 1H), 4.00-3.67 (m, 2H), 2.41-2.13 (m,2H), 2.08-1.93 (m, 1H), 1.87-1.65 (m, 1H), 1.06-0.84 (m, 12H). 24 A A A1H NMR (400 MHz, CDCl3) ? 373.03 3.08 10.27 (brs, 1H), 8.25 (d, J = 9.4Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.23 (d, J = 10.3 Hz, 1H), 5.20 (d,J = 9.6 Hz, 1H), 4.41 (t, J = 7.4 Hz, 1H), 4.09 (d, J = 11.3 Hz, 1H),3.82-3.58 (m, 1H), 0.99 (d, J = 19.5 Hz, 9H). 25 A A A 1H NMR (400 MHz,MeOD) ? 436 2.54 9.26 (dd, J = 9.0, 2.2 Hz, 1H), 8.43 (s, 1H), 8.22 (s,1H), 7.66-7.35 (m, 1H), 5.00 (m, 1H), 3.45-3.17 (m, 2H), 1.03 (m, 9H).26 A A 1H NMR (400 MHz, CDCl3) ? 9.68 (s, 449.22 2.97 1H), 8.45-8.33 (m,1H), 8.17 (d, J = 2.8 Hz, 1H), 7.88 (s, 1H), 7.36 (d, J = 10.3 Hz, 1H),6.47 (d, J = 4.9 Hz, 1H), 5.11 (d, J = 7.8 Hz, 1H), 4.90 (d, J = 10.4Hz, 1H), 3.52 (s, 1H), 3.04 (dd, J = 15.0, 10.5 Hz, 1H), 2.67 (d, J =5.0 Hz, 3H), 1.02 (s, 9H). 27 A B 1H NMR (400 MHz, CDCl3) ? 463.49 3.128.59 (dd, J = 9.7, 2.6 Hz, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 7.31 (m,1H), 5.12 (brs, 1H), 4.97 (brs, 1H), 3.33 (m, 1H), 2.70 (s, 6H), 0.95(m, 9H). 28 A A 475 3.12 29 A B 1H NMR (400 MHz, MeOD) ? 493.5 3.05 8.71(dd, J = 9.7, 2.6 Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.57 (d, J = 10.9Hz, 1H), 5.08 (d, J = 8.8 Hz, 1H), 3.54-3.40 (m, 2H), 3.32 (m, 5H), 3.15(t, J = 5.4 Hz, 2H). 1.03 (s, 9H) 30 A A 435.46 2.8 31 A A 477.65 3.2732 A A A 1H NMR (400 MHz, CDCl3) ? 348.13 1.83 10.77 (brs, 1H), 8.25 (d,J = 8.4 Hz, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 5.59 (brs,1H), 4.36 (t, J = 8.3 Hz, 2H), 4.11 (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H).33 A A A 1H NMR (400 MHz, CDCl3) ? 439.3 2.25 9.89 (brs, 1H), 8.07 (d, J= 9.3 Hz, 1H), 7.89 (s, 1H), 7.66 (m, 2H), 4.95 (t, J = 10.2 Hz, 1H),4.80 (d, J = 9.6 Hz, 1H), 3.38 (m,, 1H), 3.18-2.96 (m, 3H), 1 1.35-1.12(m, 3H), 1.08-0.90 (m, 9H). 34 A A B .1H NMR (400 MHz, CDCl3) ? 453.442.42 9.84 (s, 1H), 8.10 (d, J = 9.5 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H),7.72 (d, J = 14.2 Hz, 2H), 4.92 (m, 1H), 4.81 (m, 1H), 3.41 (d, J = 15.0Hz, 1H), 3.19-2.84 (m, 3H), 1.59-1.38 (m, 3H), 0.98 (s, 9H), 0.84 (t, J= 7.4 Hz, 3H). 35 A A B 469.18 2.11 36 B C C 390.29 1.98 37 C C C 1H NMR(300 MHz, d6-DMSO) ? 12.21 (s, 1H), 8.52 (dd, J = 9.9, 2.9 Hz, 1H),8.30-8.23 (m, J = 2.8, 1.5 Hz, 1H), 8.20 (d, J = 2.6 Hz, 1H), 8.12 (d, J= 4.1 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 4.53 (t, J = 5.4 Hz, 1H),4.44-4.27 (m, J = 9.1, 5.8 Hz, 1H), 3.77 (ddd, J = 11.0, 5.1, 3.5 Hz,1H), 3.59 (ddd, J = 11.1, 8.9, 5.8 Hz, 1H), 0.99 (s, 9H). 38 C C C 1HNMR (300 MHz, d6-DMSO) ? 425.03 2.11 12.21 (s, 1H), 8.55 (dd, J = 10.0,2.8 Hz, 1H), 8.29-8.23 (m, 1H), 8.19 (d, J = 2.7 Hz, 1H), 8.15 (d, J =4.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.77-6.69 (m, 1H), 4.88 (t, J =9.1 Hz, 1H), 3.49-3.36 (m, 1H), 3.36-3.28 (m, J = 10.5 Hz, 1H), 2.55 (t,J = 5.6 Hz, 3H), 0.98 (s, 9H). 39 A A B 1H NMR (400 MHz, CDCl3) ? 9.89(s, 453.19 2.22 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.90 (s, 1H), 7.68 (s,2H), 4.96 (t, J = 9.8 Hz, 1H), 4.76 (d, J = 9.8 Hz, 1H), 3.60 (dd, J =13.0, 6.6 Hz, 1H), 3.42 (m, 1H), 3.09-2.86 (m, 1H), 1.20 (d, J = 4.9 Hz,6H), 0.97 (s, 9H). 40 A A B 467.2 2.36 41 A A B 386.39 3.09 42 A A A 1 HNMR (300 MHz, CDCl3) ? 426.31 3.27 10.70 (s, 1H), 8.42 (dd, J = 9.6, 2.6Hz, 1H), 8.05 (s, 1H), 7.73 (s, 1H), 7.40 (t, J = 8.4 Hz, 1H), 5.32 (d,J = 6.6 Hz, 1H), 4.83 (t, J = 9.4 Hz, 1H), 2.89 (d, J = 5.3 Hz, 1H),2.34 (dd, J = 12.8, 9.6 Hz, 1H), 1.92-1.37 (m, 8H), 1.32-1.24 (m, 1H),1.20-1.06 (m, 3H). 43 A A A 1H NMR (300 MHz, CDCl3) ? 426.47 2.49 11.16(s, 1H), 8.70 (s, 1H), 8.04 (d, J = 3.2 Hz, 1H), 7.96 (s, 1H), 7.87 (s,1H), 5.02 (d, J = 8.1 Hz, 1H), 4.80 (t, J = 9.6 Hz, 1H), 2.81 (d, J =9.9 Hz, 1H), 2.34 (t, J = 11.3 Hz, 1H), 1.14 (s, 9H). 44 A B B 1H NMR(400 MHz, DMSO) ? 374.02 2.1 12.26 (s, 2H), 8.55 (d, J = 9.7 Hz, 1H),8.19 (dd, J = 45.1, 15.8 Hz, 3H), 7.48 (d, J = 8.1 Hz, 1H), 4.79 (s,1H), 2.58 (dd, J = 20.6, 12.2 Hz, 2H), 1.85 (ddd, J = 29.4, 26.5, 21.1Hz, 7H). 45 B A C 1H NMR (300 MHz, CDCl3) ? 362.39 1.89 10.42 (s, 1H),8.47 (dd, J = 9.3, 2.7 Hz, 1H), 8.13 (d, J = 11.2 Hz, 1H), 8.10 (s, 1H),8.04 (d, J = 3.2 Hz, 1H), 4.89 (d, J = 9.0 Hz, 1H), 4.26 (t, J = 9.9 Hz,1H), 3.65 (d, J = 9.2 Hz, 1H), 3.54 (td, J = 11.4, 2.9 Hz, 1H),2.17-1.99 (m, 1H), 1.40 (dd, J = 14.0, 11.9 Hz, 1H), 0.96 (d, J = 18.4Hz, 9H), 0.90-0.73 (m, 1H). 46 A B C 1H NMR (400 MHz, CDCl3) ? 9.38 (s,410.19 2.03 1H), 8.53 (d, J = 6.9 Hz, 1H), 8.16 (m, 2H), 8.06 (s, 1H),5.09-4.89 (m, 1H), 3.42-3.31 (m, 1H), 3.11 (m, 1H), 2.84 (s, 3H), 1.00(s, 9H). 47 A A B 1H NMR (400 MHz, MeOD) ? 358.02 2.17 8.70 (dd, J =8.9, 2.3 Hz, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 7.99 (d, J = 7.3 Hz, 1H),6.60 (d, J = 7.2 Hz, 1H), 5.05 (d, J = 10.7 Hz, 1H), 2.93 (dd, J = 15.9,1.8 Hz, 1H), 2.53 (dd, J = 15.9, 11.2 Hz, 1H), 1.08 (d, J = 0.8 Hz, 9H)48 A B B 1H NMR (400 MHz, MeOD) ? 359.02 2.12 8.63-8.45 (m, 2H), 7.96(d, J = 7.3 Hz, 2H), 6.66 (d, J = 7.3 Hz, 2H), 4.95 (d, J = 10.6 Hz,2H), 2.84 (dd, J = 15.4, 2.4 Hz, 2H), 2.44 (dd, J = 15.9, 10.7 Hz, 2H),0.98 (s, 9H). 49 A A B 1H NMR (300 MHz, MeOD) ? 8.73 (t, 364.44 2.1 J =5.0 Hz, 1H), 8.44 (s, 1H), 8.37-8.22 (m, 2H), 4.69 (dd, J = 9.9, 2.9 Hz,1H), 4.11 (dd, J = 11.5, 3.1 Hz, 1H), 3.83 (dd, J = 11.4, 10.0 Hz, 1H),3.32 (dt, J = 3.3, 1.6 Hz, 1H), 1.12 (s, 9H). 50 A A B 402.45 1.98(diastereomer of Compounds 51 and 52) 51 A A C 402.45 2.06 (diastereomerof Compounds 50 and 52) 52 A A B 402.25 2.16 (diastereomer of Compounds50 and 51) 53 A A B 1H NMR (400 MHz, DMSO) ? 377.42 2.5 12.57 (s, 1H),9.40 (s, 1H), 8.88 (s, 1H), 8.40 (d, J = 18.7 Hz, 2H), 8.34 (s, 1H),3.93 (s, 1H), 3.52 (s, 1H), 1.20 (s, 9H). 54 A A B 1H NMR (400 MHz,DMSO) ? 427.4 2.92 12.65 (s, 1H), 12.41 (s, 1H), 9.28 (s, 1H), 8.86 (s,1H), 8.65 (s, 1H), 8.30 (d, J = 3.5 Hz, 2H), 3.97-3.70 (m, 1H), 3.51 (s,1H), 1.18 (s, 9H) 55 A A B 400.46 1.94 56 A A A 1 H NMR (400 MHz, DMSO)? 393.32 2.7 12.65 (s, 1H), 9.43 (s, 1H), 9.15 (s, 1H), 8.44 (d, J = 4.7Hz, 1H), 8.41-8.29 (m, 2H), 3.93 (s, 1H), 3.54 (s, 1H), 1.19 (d, J =20.0 Hz, 9H). 57 A A A 1H NMR (400 MHz, CDCl3) ? 8.05 (d, 475.23 2.26 J= 7.9 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.55 (s, 1H),5.87 (t, J = 54.9 Hz, 1H), 5.03 (t, J = 10.4 Hz, 1H), 4.86 (m, 1H), 3.68(brs, 1H), 3.43 (m, 2H), 3.19 (m, 1H), 0.94 (s, 9H). 58 A A A NMR (400MHz, CDCl3) ? 493.31 2.37 8.03 (dd, J = 9.3, 2.4 Hz, 1H), 7.82 (t, J =11.2 Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 5.07 (t, J = 10.6 Hz, 1H),4.77 (m, 1H), 3.45 (m, 1H), 3.16-2.99 (m, 1H), 0.97-0.86 (m, 9H). 59 A AB 1H NMR (300 MHz, MeOD) ? 8.54 (s, 388.23 2.21 1H), 8.50-8.18 (m, 3H),7.18 (dd, J = 15.7, 7.1 Hz, 1H), 6.08 (dd, J = 15.7, 1.3 Hz, 1H), 5.21(t, J = 22.5 Hz, 1H), 1.12 (s, 9H). 60 A B C 454.21 2.01 61 A A B 1H NMR(300 MHz, MeOD) ? 8.95 (s, 470.14 2.23 1H), 8.29-8.14 (m, 2H), 8.08 (d,J = 4.0 Hz, 1H), 5.26 (m, 1H), 4.21 (d, J = 15.3 Hz, 1H), 3.92 (dd, J =30.0, 14.5 Hz, 2H), 3.77-3.57 (m, 1H), 1.10 (s, 9H). 62 A B B 416.042.15 63 A A A 389.06 2.08 64 A C 1H NMR (400 MHz, MeOD) ? 438.25 1.938.60-8.52 (m, 1H), 8.46 (s, 1H), 8.32 (d, J = 5.3 Hz, 2H), 5.16 (m, 2H),4.00 (d, J = 14.7 Hz, 1H), 3.80 (d, J = 14.7 Hz, 1H), 3.59 (d, J = 13.9,1H), 1.12 (s, 9H). 65 A A B 416.07 2.11 66 A A B 1H NMR (400 MHz, CDCl3)? 430.47 2.37 (diastereomer 10.15 (s, 1H), 8.49 (dd, J = 9.3, 2.6 Hz,1H), of Compound 8.16 (s, 1H), 8.10 (d, J = 2.6 Hz, 1H), 67) 8.06 (d, J= 3.0 Hz, 1H), 5.30 (d, J = 15.0 Hz, 1H), 5.19-5.10 (m, 1H), 4.32-4.24(m, 1H), 4.23-4.17 (m, 1H), 2.37 (dt, J = 14.9, 3.4 Hz, 1H), 1.85-1.71(m, 2H), 1.09 (s, 9H). 67 A A B 1H NMR (400 MHz, CDCl3) ? 9.40 (s,430.44 2.42 (diastereomer 1H), 8.47 (dd, J = 9.3, 2.7 Hz, 1H), ofCompound 8.15 (s, 1H), 8.10 (d, J = 2.7 Hz, 1H), 66) 7.99 (d, J = 2.8Hz, 1H), 5.54 (s, 1H), 4.84 (d, J = 7.5 Hz, 1H), 4.23 (t, J = 9.9 Hz,1H), 3.91 (s, 1H), 2.07-1.97 (m, 1H), 1.62 (t, J = 13.0 Hz, 1H), 1.01(s, 9H). 68 B A B 1H NMR (400 MHz, MeOD) ? 8.51 (d, 429.26 1.9 J = 8.0Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.93 (d, J = 3.5 Hz, 1H), 7.38 (s,1H), 5.08 (m, 1H), 5.00-4.90 (m, 1H), 4.74 (s, 2H), 4.60 (m, 1H), 1.2(s, 9H). 69 B B C 1H NMR (300 MHz, MeOD) ? 426.09 1.81 8.59-8.39 (m,2H), 8.32 (t, J = 5.3 Hz, 2H), 4.59 (d, J = 9.5 Hz, 2H), 2.21 (s, 1H),1.79 (dddd, J = 28.6, 23.0, 13.2, 6.9 Hz, 3H), 1.11 (d, J = 9.5 Hz, 9H).70 A A B 1H NMR (400 MHz, DMSO) ? 392.46 1.76 (diastereomer 8.61 (dd, J= 9.9, 2.6 Hz, 1H), 8.26 (s, 1H), of Compound 8.18 (s, 1H), 8.11 (d, J =4.1 Hz, 1H), 71) 4.66 (d, J = 10.4 Hz, 1H), 4.43 (s, 1H), 4.29 (d, J =4.1 Hz, 1H), 4.04 (s, 1H), 3.35 (s, 1H), 3.26 (d, J = 6.1 Hz, 2H), 1.69(t, J = 12.3 Hz, 1H), 1.59-1.45 (m, 1H), 0.96 (s, 9H). 71 A A A 1H NMR(400 MHz, MeOD) ? 392.46 1.79 (diastereomer 8.61 (dd, J = 9.6, 2.7 Hz,1H), 8.17 (s, 2H), of Compound 8.01 (d, J = 4.1 Hz, 1H), 4.53 (d, J =10.0 Hz, 70) 1H), 3.75-3.56 (m, 2H), 3.48 (dd, J = 11.0, 6.3 Hz, 1H),2.08-1.97 (m, 1H), 1.75 (dt, J = 28.7, 9.4 Hz, 1H), 1.04 (s, 9H). 72 C1H NMR (400 MHz, CDCl3) ? 9.99 (s, 376.46 1.93 (diastereomer 1H), 8.60(dd, J = 9.4, 2.7 Hz, 1H), of Compound 8.26 (s, 1H), 8.20 (d, J = 2.6Hz, 1H), 73) 8.10 (d, J = 3.2 Hz, 1H), 5.06 (t, J = 12.3 Hz, 1H), 4.28(dd, J = 9.6, 7.2 Hz, 1H), 3.96 (d, J = 5.7 Hz, 1H), 2.71 (s, 1H), 1.97(ddd, J = 14.2, 5.8, 2.9 Hz, 1H), 1.66 ? 1.58 (m, 1H), 1.28 (dd, J =6.5, 5.5 Hz, 4H), 1.04 (d, J = 10.1 Hz, 9H). 73 C B C 1H NMR (400 MHz,CDCl3) ? 376.46 2.01 (diastereomer 10.81 (s, 1H), 8.47 (dd, J = 9.3, 2.7Hz, 1H), of Compound 8.14 (s, 1H), 8.05 (dd, J = 8.4, 2.9 Hz, 72) 2H),4.95 (s, 1H), 4.81 (d, J = 8.3 Hz, 1H), 4.31 ? 4.14 (m, 1H), 3.72 (dd, J= 8.9, 6.0 Hz, 1H), 1.83 ? 1.70 (m, 1H), 1.48 ? 1.32 (m, 1H), 1.24 ?1.11 (m, 4H), 0.98 (s, 9H). 74 B B B 1H NMR (300 MHz, MeOD) ? 374.421.94 8.59 (dd, J = 9.6, 2.9 Hz, 1H), 8.15 (d, J = 2.7 Hz, 2H), 8.01 (d,J = 4.1 Hz, 1H), 4.60 (dd, J = 8.3, 6.0 Hz, 1H), 2.90-2.68 (m, 2H), 1.17(s, 3H), 0.85 (dt, J = 9.7, 6.7 Hz, 1H), 0.64 (dt, J = 9.4, 4.9 Hz, 1H),0.47-0.33 (m, 1H), 0.27 (ddd, J = 21.3, 12.8, 10.1 Hz, 1H). 75 C B C456.45 2.55 76 B A B 1H NMR (300 MHz, MeOD) ? 394.45 1.87 8.70 (dd, J =9.7, 2.8 Hz, 1H), 8.15 (dd, J = 6.1, 4.0 Hz, 2H), 8.02 (d, J = 4.1 Hz,1H), 5.23 (dd, J = 10.7, 3.1 Hz, 1H), 4.30 (d, J = 47.9 Hz, 2H), 3.63(d, J = 18.2 Hz, 1H), 3.31 (dt, J = 3.3, 1.6 Hz, 3H), 2.83 (dd, J =15.3, 3.3 Hz, 1H), 2.63 (dd, J = 15.3, 10.8 Hz, 1H), 1.07 (s, 6H). 77 CB C 1H NMR (400 MHz, CDCl3) ? 9.55 (s, 444.36 2.77 1H), 8.58 (dd, J =9.3, 2.5 Hz, 1H), 8.18 (s, 2H), 8.00 (d, J = 2.7 Hz, 1H), 5.13 (brs,1H), 4.95 (t, J = 8.2 Hz, 1H), 3.84 (m, 2H), 2.72 (m, 1H), 2.38 (m, 1H),1.67-1.15 (m, 10H), 0.94 (m, 3H). 78 A A B 1H NMR (400 MHz, MeOD) ?416.27 2.2 8.78 (dd, J = 9.7, 2.7 Hz, 1H), 8.16 (s, 2H), 7.99 (d, J =4.1 Hz, 1H), 5.20 (d, J = 9.9 Hz, 1H), 2.86-2.69 (m, 1H), 2.53 (dd, J =14.7, 11.0 Hz, 1H), 1.76-1.56 (m, 2H), 1.53 (m, 4H), 1.29 (m, 4H), 1.02(s, 3H). 79 B A B H NMR (300.0 MHz, MeOD) d 430.41 2.22 8.66 (d, J = 8.9Hz, H), 8.29 (s, H), 8.22-8.18 (m, H), 5.49 (s, H), 4.16-4.06 (m, H),2.97 (s, H), 2.92 (s, H), 2.86-2.78 (m, H), 2.45 (s, H), 2.06 (s, H),1.93 (s, H), 1.80 (s, H) and 1.27-1.21 (m, 6 H) ppm 80 C B C 1H NMR (400MHz, CDCl3) ? 406.09 2.41 8.66 (dd, J = 9.2, 2.6 Hz, 1H), 8.53 (d, J =9.6 Hz, 2H), 8.43 (s, 1H), 8.36 (s, 1H), 5.27-5.13 (m, 1H), 3.60 (s,3H), 3.02-2.87 (m, 2H), 1.94 (s, 1H), 1.06 (s, 9H). 81 C C C 1H NMR (300MHz, CDCl3) ? 9.83 (s, 440.45 2.35 1H), 8.58 (dd, J = 9.3, 2.7 Hz, 1H),8.37 (s, 1H), 8.25 (s, 1H), 8.13 (d, J = 3.3 Hz, 1H), 5.66 (s, 1H),5.32-5.16 (m, 1H), 4.71-4.32 (m, 4H), 4.04 (q, J = 7.1 Hz, 2H),2.94-2.77 (m, 1H), 2.70 (dd, J = 15.1, 9.1 Hz, 1H), 1.26 (s, 3H),1.08-1.04 (t, J = 7.1 Hz, 3 H). 82 C C C 1H NMR (400 MHz, CDCl3) ? 9.93(s, 460.29 3.08 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H),8.18 (s, 1H), 8.00 (d, J = 3.4 Hz, 1H), 5.19 (m, 1H), 4.98 (m, 1H),3.98-3.65 (m, 2H), 2.73 (dd, J = 14.3, 3.6 Hz, 1H), 2.38 (m, 1H),1.69-1.23 (m, 10H), 0.93 (t, J = 6.8, 3H). 83 B A B 1H NMR (400 MHz,MeOD) ? 9.05 (d, 432.36 2.37 J = 2.1 Hz, 1H), 8.39-8.24 (m, 2H), 8.16(d, J = 4.9 Hz, 1H), 5.23 (d, J = 10.4 Hz, 1H), 2.86 (d, J = 15.6 Hz,1H), 2.65 (m, 1H), 1.58 (m,, 7H), 1.37 (m, 3H), 1.05 (s, 3H). 84 B B C1H NMR (300 MHz, MeOD) ? 412.43 1.9 8.67 (dd, J = 9.6, 2.8 Hz, 1H), 8.16(m, 2H), 8.04 (d, J = 4.0 Hz, 1H), 5.38 (dd, J = 10.8, 3.2 Hz, 1H),4.72-4.23 (m, 4H), 2.86 (dd, J = 15.5, 3.3 Hz, 1H), 2.70 (dd, J = 15.5,10.9 Hz, 1H), 1.15 (s, 3H). 85 B A C 1H NMR (400 MHz, MeOD) ? 392.1 2.238.68 (dd, J = 9.3, 2.7 Hz, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 8.32 (s,1H), 5.17 (dd, J = 9.8, 3.5 Hz, 1H), 2.87 (m, 2H), 1.06 (s, 9H). 86 A AB 1H NMR (400 MHz, MeOD) ? 454.34 2.4 8.75 (dd, J = 9.7, 2.7 Hz, 1H),8.18 (s, 2H), 8.00 (d, J = 4.2 Hz, 1H), 2.81 (dd, J = 15.2, 3.1 Hz, 1H),2.55 (dd, J = 15.2, 10.8 Hz, 1H), 2.00 (m, 3H), 1.82-1.49 (m, 12H). 87 AA A 389.13 2.02 88 A A B 388.36 2.01 89 A A B 383.38 2.1 90 A A B 1H NMR(300 MHz, DMSO) ? 8.68 (s, 372.5 1.8 1H), 8.43 (d, J = 14.1 Hz, 2H),8.23 (s, 1H), 4.96 (s, 2H), 2.88-2.55 (m, 4H), 2.45 (s, 3H), 1.00 (s,9H). 91 A A B 374.42 1.96 92 B B C 374.42 1.94 93 B B C 428.49 2.37 94 AA A 1H NMR (400 MHz, MeOD) ? 9.02 (d, 470.27 2.6 J = 2.3 Hz, 1H),8.40-8.24 (m, 2H), 8.18 (d, J = 5.0 Hz, 1H), 4.91 (d, J = 11.6 Hz, 1H),2.88 (dd, J = 16.0, 2.8 Hz, 1H), 2.65 (dd, J = 15.9, 11.0 Hz, 1H), 2.01(s, 3H), 1.77 (dd, J = 27.9, 11.9 Hz, 12H). 95 A A B 1H NMR (400 MHz,MeOD) ? 414.28 2.12 8.62 (dd, J = 9.3, 2.6 Hz, 1H), 8.48 (t, J = 5.4 Hz,1H), 8.32 (s, 1H), 8.29 (d, J = 5.5 Hz, 1H), 5.42 (dd, J = 10.0, 3.4 Hz,1H), 2.84 (m, 2H), 2.18 (s, 1H), 1.65 (m, 4H), 1.39 (m, 6H). 96 A A B407.37 2.79 97 A A A ¹H NMR (300 MHz, MeOD) δ 8.95 (d, 393.43 2.5 J =2.3 Hz, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.35 (d, J = 5.2 Hz, 1H), 5.12(dd, J = 10.7, 2.9 Hz, 1H), 2.93 (dd, J = 16.5, 2.9 Hz, 1H), 2.73 (dd, J= 16.4, 10.7 Hz, 1H), 1.10 (s, 9H); LCMS Gradient 10-90%, 0.1% formicacid, 5 minutes, C18/ACN, Retention Time = 2.79 min, (M + H) 407.37

TABLE 2 IC₅₀, EC₅₀, NMR and LCMS Data of Compounds of WO2005/095400 MDCKcell bDNA bDNA Compounds Molecule IC50 (uM) EC50 (uM) EC99 (uM) C1

 >20 (C) C2

 >20 (C) C3

 >20 (C) 3.38 (C)   9.37 (C) C4

2.33 (B)  6.4 (C) >16.7 (C)

Example 3 In Vivo Assay

For efficacy studies, Balb/c mice (4-5 weeks of age) were challengedwith 5×10³ TCID₅₀ in a total volume of 50 μl by intranasal by intranasalinstillation (25 μl/nostril) under general anesthesia(Ketamine/Xylazine). Uninfected controls were challenged with tissueculture media (DMEM, 50 μl total volume). 48 hours post infection micebegan treatment with Compounds 1 and 2 at 30 mg/kg bid for 10 days. Bodyweights and survival is scored daily for 21 days. In addition, WholeBody Plethysmography is conducted approximately every third dayfollowing challenge and is reported as enhanced pause (Penh). TotalSurvival, Percent Body Weight Loss on post challenge day 8 and Penh onstudy day 6/7 are reported.

TABLE 3 Influneza Therapeutic Mouse Model (Dosing @ 48 hours postinfection with 30 mg/kg BID X 10 days) Percent Percent Weight WBPCompounds Survival Loss (Day 8)¹ (Penh; Day 6)² 1 100 26.6 1.88 2 100 142.03 ¹Average weight loss for untreated controls on day 8 is 30-32%.²Average Penh scores for untreated controls on study day 6 or 7 is2.2-2.5, and for uninfected mice is ~0.35-0.45.

Example 4 Synergistic/Antagonism Analyses

For synergy/antagonism analysis, test compounds were evaluated in athree day MDCK cell CPE-based assay, infected with A/Puerto Rico/8/34 atan MOI of 0.01, in combination experiments with either the neuraminidaseinhibitors oseltamivir carboxylate or zanamivir, or the polymeraseinhibitor T-705 (see, e.g., Ruruta et al., Antiviral Reasearch, 82:95-102 (2009), “T-705 (flavipiravir) and related compounds: Novelbroad-spectrum inhibitors of RNA viral infections”), using the Blissindependence method (Macsynergy, Pritchard and Shipman, 1990). See,e.g., Prichard, M. N. and C. Shipman, Jr., A three-dimensional model toanalyze drug-drug interactions. Antiviral Res, 1990. 14(4-5): p.181-205. This standard method involves testing different concentrationcombinations of inhibitors in a checkerboard fashion and a synergyvolume is calculated by comparing the observed response surface with theexpected result calculated from simple additivity of the single agentsalone. Synergy volumes greater than 100 are considered strong synergyand volumes between 50 and 100 are considered moderate synergy. Synergyvolumes of zero represent additivity and negative synergy volumesrepresent antagonism between the agents.

TABLE 4 Synergy/Antagonism Data Combination experiments using the BlissIndependence (Macsynergy) Method Synergy Volume, Bliss Independence 95%Confidence Result Compound 1 + oseltamivir 360 strong synergy Compound1 + favipiravir 1221 strong synergy Compound 1 + zanamivir 231 strongsynergy Compound 2 + oseltamivir 250 strong synergy Compound 2 +favipiravir 100 synergy Compound 2 + zanamivir 220 strong synergyCompound 14 + oseltamivir 545 strong synergy Compound 14 + favipiravir349 strong synergy Compound 14 + zanamivir 255 strong synergy Compound57 + oseltamivir 268 strong synergy Compound 57 + favipiravir 430 strongsynergy Compound 57 + zanamivir 171 strong synergy Compound 87 +oseltamivir 348 strong synergy Compound 87 + favipiravir 412 strongsynergy Compound 87 + zanamivir 2.7 insignificant

All references provided herein are incorporated herein in its entiretyby reference. As used herein, all abbreviations, symbols and conventionsare consistent with those used in the contemporary scientificliterature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manualfor Authors and Editors, 2nd Ed., Washington, D.C.: American ChemicalSociety, 1997.

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.